Methods of inhibitng gastric secretion with prostaglandin derivatives

ABSTRACT

A therapeutic method for inhibiting gastric secretion in an individual for whom such therapy is indicated is disclosed. The method comprises administering to such an individual an effective inhibitory amount of certain derivatives of 15-deoxy-16-hydroxy-prostaglandin E 1  esters.

This is a division of application Ser. No. 712,910 filed Mar. 15, 1985now U.S. Pat. No. 4,472,080; which is a continuation of application Ser.No. 549,090 filed Nov. 7, 1983, now abandoned; which is a division ofapplication Ser. No. 357,428 filed Mar. 12, 1983, now U.S. Pat. No.4,415,592; which is a division of application Ser. No. 215,802 filedDec. 12, 1980, now U.S. Pat. No. 4,331,688; which is a division ofapplication Ser. No. 973,010 filed Dec. 12, 1978, now U.S. Pat. No.4,275,224; which is a division of application Ser. No. 880,501 filedFeb. 23, 1978, now U.S. Pat. No. 4,132,738.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

The compounds of this invention are analogues of natural prostaglandins.

Natural prostaglandins are alicyclic compounds related to prostanoicacid, the structure of which is: ##STR1## By convention, the carbonatoms of I are numbered sequentially from the carboxylic carbon atom. Animportant stereochemical feature of I is the trans-orientation of thesidechains C₁ -C₇ and C₁₃ -C₂₀, an orientation common to all naturalprostaglandins. In I, as elsewhere in this specification, solid lines(--) provide a reference plane (such as the cyclopentyl ring or thebonds among atoms C₁ -C₇ and C₁₃ -C₂₀); a dashed line (- - - -)indicates projection of a covalent bond below such reference plane(alpha-configuration); while a wedged line ( ) represents directionabove such plane (beta-configuration). Those conventions apply to allstructural formula subsequently discussed in this specification. In somestructures, however, a swung dash or serpentine line ( ) denotesorientation of a covalent bond either above or below a plane orreference (indicated by the Greek letter χι in the nomenclature of suchstructures).

Natural prostaglandins have the general structure, ##STR2## in which: Land M may be ethylene or cis-vinylene radicals; and the cyclopentyl ring##STR3## may be: ##STR4##

Formula II and all representations of the cyclopentyl moiety depict thenat-isomer, i.e., the C₇ -C₈ bond in the alpha-configuration and the C₁₂-C₁₃ bond in the beta-configuration. In the ent-isomer (which does notoccur in nature), the direction of the bonds at C₇ -C₈ and C₁₂ -C₁₃ isreversed.

Prostaglandins are classified according to the functional groups presentin the five-membered ring and the presence of double bonds in the ringor chains. Prostaglandins of the A-class (PGA or prostaglandins A) arecharacterized by an oxo group at C₉ and a double bond at C₁₀ -C₁₁(Δ¹⁰,11); those of the B-class (PGB) have an oxo group at C₉ and adouble bond at C₈ -C₁₂ (Δ⁸,12); compounds of the C-class (PGC) containan oxo group at C₉ and a double bond at C₁₁ -C₁₂ (Δ¹¹,12); members ofthe D-class (PGD) have an oxo group at C₁₁ and an alpha-oriented hydroxygroup at C₉ ; prostaglandins of the E-class (PGE) have an oxo group atC₉ and an alpha-oriented hydroxyl group at C₁₁ ; and members of theF.sub.α -class (PGF.sub.α) have an alpha-directed hydroxyl group at C₉and an alpha-oriented hydroxyl group at C₁₁. Within each of the A, B, C,D, E, and F classes of prostaglandins are three subclassifications basedupon the presence of double bonds in the side-chains at C₅ -C₆, C₁₃-C₁₄, or C₁₇ -C₁₈. The presence of a trans-unsaturated bond only at C₁₃-C₁₄ is indicated by the subscript numeral 1; thus, for example, PGE₁(or prostaglandin E₁) denotes a prostaglandin of the E-type (oxo-groupat C₉ and an alpha-hydroxyl at C₁₁) with a trans-double bond at C₁₃-C₁₄. The presence of both a trans-double bond at C₁₃ -C₁₄ and acis-double bond at C₅ -C₆ is denoted by the subscript numeral 2; forexample, PGE₂. Lastly, a trans-double bond at C₁₃ -C₁₄, a cis-doublebond at C₅ -C₆ and a cis-double bond at C₁₇ -C₁₈ is indicated by thesubscript numeral 3; for example PGE₃. The above notations apply toprostaglandins of the A, B, C, D, and F series as well; however, in thelast, the alpha-orientation of the hydroxyl group at C₉ is indicated bythe subscript Greek letter α after the numeral subscript.

Nomenclature of prostaglandins and their analogues deserves note insofaras there are three current systems followed in the scientific and patentliterature. One system for convenience referred to as the Nelson system,uses the trivial names of prostaglandins and designates analogues bymodifications of the trivial names (see--J. Med. Chem., 17; 911 [1974]).Another system follows the rules of the International Union of Pure andApplied Chemistry (IUPAC) and refers to prostaglandins and theiranalogues as derivatives of heptanoic acid. A third system employs aconvention of Chemical Abstracts ("CA") that designates prostaglandinsand derivatives thereof as derivatives of prostanoic acid. An example ofeach system is provided below for the following structure: ##STR5## Inthe Nelson system, III is designated prostaglandin F₃α or PGF₃α(shortened form); in the IUPAC system,7-[3R,5S-dihydroxy-2R-(3S-hydroxy-1E,5Z-octadienyl)-cyclopent-1R-y1]-5Z-heptenoic acid; in the CA system,(5Z,9α,11α,13E,15S,17Z)-9,11,15-trihydroxyprosta-5,13,17-trien-1-oicacid.

It is important to note that in all natural prostaglandins there is ahydroxyl group at C₁₅ oriented below the plane in which C₁₅ is located.In the Cahn-Ingold-Prelog system of defining stereochemistry, that C₁₅hydroxyl group is in the S-configuration. Inversion of the orientationof the C₁₅ hydroxyl group such that the group projects above the planein which the C₁₅ atom is located represents the R-configuration. TheCahn-Ingold-Prelog system is used to define stereochemistry of anyasymmetric center outside of the carbocyclic ring in all three systemsof nomenclature described above. In some literature, however, α,βdesignations are used for such centers.

Isomerism of a double bond is designated in all three systems by use ofconventional prefixes cis- or trans-, or their respective equivalents, Zor E (as suggested in J. Am. Chem. Soc., 59: 509 [1968).

For details of other conventions utilized in nomenclature ofprostaglandins, see: Nelson, N. A., "Prostaglandin Nomenclature", J.Med. Chem., 17: 911 (1974).

Recent research indicates that prostaglandins appear ubiquitously inanimal tissues and elicit biochemical and physiological effects in avariety of mammalian systems.

In the endocrine system, for example, experimental evidence indicatesprostaglandins influence the hormone synthesis or release of hormones inthe secretory glands. In rats, PGE₁ and PGE₂ increase the release of thegrowth hormone while PGA₁ increases its synthesis. In sheep, PGE₁ andPGF₁α inhibit ovarian progesterone secretion. In a variety of mammals,PGF₁α and PGF₂α act as luteolytic factors. In mice, PGE₁, PGE₂, PGF₁αand PGF₁β increase thyroid activity. In hypophysectomized rats, PGE₁,PGE₂ and PGF₁α stimulate stereoidogenesis in the adrenal glands.

In the mammalian male reproductive system, PGE₁ contracts the smoothmuscle of the vas deferens. In the female reproductive system, PGE andPGF.sub.α compounds contract uterine smooth muscle. In general, PGE, PGBand PGA compounds relax in vitro human uterine muscle strips, whilethose of the PGF.sub.α class contract such isolated preparations. PGEcompounds, in general, promote fertility in the female reproductivesystem while PGF₂α has contragestational effects. PGF₂α also appears tobe involved in the mechanism of menstruation. In general, PGE₂ producespotent oxytocic effects in inducing labor, while PGF₂α inducesspontaneous abortions in early pregnancy.

PGF.sub.α and PGE compounds have been isolated from a variety of nervoustissues. PGE₁ retards whereas PGF₂α facilitates transmission along motorpathways in the central nervous system. PGE₁ and PGE₂ reportedly inhibittransmitter release from adrenergic nerve endings in the guinea pig.

Prostaglandins stimulate contraction of gastrointestinal smooth musclein vivo and in vitro. In dogs, PGA₁, PGE₁, and PGE₂ inhibit gastricsecretion. PGA₁ exhibits similar activity in man. Natural prostaglandinsand some of their analogues also protect gastric mucosa from ulcerationinduced by nonsteroidal antiinflammatory agents.

In most mammalian respiratory tracts, PGE and PGF compounds affect invitro preparations of tracheal smooth muscle. Specifically, PGE₁ andPGE₂ relax while PGF₂α contracts such smooth muscle. The human lungnormally contains PGE and PGF compounds; consequently, some cases ofbronchial asthma may involve an imbalance in the production ormetabolism of those compounds.

Prostaglandins are involved in certain hematic mechanisms in mammals.PGE₁, for example, inhibits aggregation of blood platelets in vitro.

In a variety of mammalian cardiovascular systems, compounds of the PGEand PGA classes are vasodilators whereas those of the PGF.sub.α classare vasoconstrictors, by virtue of their action on vascular smoothmuscle.

Prostaglandins naturally appear in the kidney and reverse experimentaland clinical renoprival hypertension.

The prostaglandins and their analogues have broad clinical implications.In obstetrics and gynecology, they may find use in fertility control,treatment of menstrual disorders, the induction of labor, and thecorrection of hormone disorders. In gastroenterology, they may helptreat or prevent peptic ulcers and various disorders involving motility,secretion, and absorption in the gastrointestinal tract. They may, inthe respiratory area, prove beneficial in the therapy of bronchialasthma and other diseases involving bronchoconstriction. In hematology,they may display utility as anti-clotting agents in diseases such asvenous thrombosis, thrombotic coronary occlusion and other diseasesinvolving thrombi. For circulatory diseases, they have therapeuticutility in hypertension, peripheral vasopathies and cardiac disorders.

The following references include a more complete review of the chemical,physiological and pharmacological aspects of the prostaglandins: TheProstaglandins, Vol. I., P. Ramwell, Ed., New York, Plenum Press, 1973;Ann. N.Y. Acad. Sci., 180: 1-568 (1971); Higgins and Braunwald, J. Am.Med. Assn., 53: 92-112 (1972); Osterling, Marozowich, and Roseman, J.Phar. Sci., 61: 1861-1895 (1972); and Nakano, Resident and Staff Phys.,19: 92, 94-99, and 102-106 (1973).

DESCRIPTION OF THE PRIOR ART

A. Prior art relevant to the claimed carbinol 16-hydroxy prostaglandinanalogues is disclosed in published Netherlands application No.75-03553, U.S. application Ser. No. 454,913 assigned to G. D. Searle &Co., hereafter referred to as "Searle". Searle is directed to 16-hydroxyprostaglandin analogues which are acids and esters. Searle's broadgeneric disclosure is represented by: ##STR6## where R₁, R₂, R₃, R₄, R₆and R₇ can be hydrogen or a lower-alkyl radical and R₈ is an alkyl groupcontaining 3-5 carbon atoms or a cycloalkly group containing 5-7 carbonatoms.

Compounds disclosed by Searle which are most structurally similar to theclaimed compounds of the present invention are shown below.

Searle Example 12 ##STR7## Racemic methyl7-[3(R)-hydroxy-2β-(4(R)-hydroxy-trans-1-octenyl)-5-oxocyclopentane]-1α-heptanoate(the methyl ester analogous to presently claimed TR 4706, a carbinolanalogue). Searle Example 14 ##STR8## Racemic methyl7-[3(R)-hydroxy-2β-(4-(RS)-4-hydroxy-4-methyl-trans-1-octenyl)-5-oxocyclopentane]-1α-heptanoate(the methyl ester analogous to presently claimed TR 4698, a carbinolanalogue).

Searle generally discloses that the acids and esters disclosed andclaimed display an ability to " . . . inhibit the gastric secretionstimulated by secretogogues such as histamine and pentagastrin while . .. lacking the potent undesirable side-effects displayed by relatedsubstances. In addition, these compounds are inhibitors of bloodplatelet aggregation and, moreover, display anti-fertility andbronchodilating properties." No biological data relating to the activityof any compounds disclosed and/or claimed by Searle is presented.

Searle also discloses compounds having a methylene group adjacent toC-16 and a cycloalkyl group attached thereto.

Searle Example 22 ##STR9## Methyl7-[3(R)-hydroxy-2β-(4-(RS)-4-cyclohexylmethyl)-4-hydroxy-4-methyl-1-trans-1-butenyl)-5-oxocyclopentane]-1α-heptanoate.Searle Example 43 ##STR10## Racemic methyl7-[2β-(4(RS)-4-cyclohexylmethyl-4-methyl-4-hydroxy-trans-1-butenyl)-5-oxocyclopent-3-ene]-1α-heptanoate.

The two cycloalkyl compounds disclosed by Searle are both esters. Inaddition, at least one methylene group separates the cycloalkyl moietyfrom the C-16 position.

As disclosed in detail hereinafter, applicants comparative biologicaltesting of the alkyl-substituted ester prostaglandin analogues disclosedby Searle with applicants alkyl-substituted carbinols indicates that thealkyl-substituted carbinols exhibit a significant reduction inundesirable side-effects.

B. Other prior art relevant to the claimed carbinol 16-hydroxyprostaglandin analogues is published Netherlands application No.73-10776, U.S. application Ser. No. 274,769, assigned by Lederle toAmerican Cyanamid Company, (hereafter referred to as "Lederle". Lederlediscloses acids and esters of 16-hydroxy prostaglandin analogues. Thecompounds of Lederle are represented by the following formula: ##STR11##wherein R₃ is hydroxy or alkoxy and R₂ can be --C═C₄ --CH₂ --R" where R"is a straight chain alkyl having from 2 to 10 carbon atoms substitutedwith an hydroxy triphenylmethoxy group or a straight chain alkyl having2 to 6 carbon atoms and one branched group of 1 to 3 carbon atoms.Numerous examples of 16hydroxy-acid and ester prostaglandin analoguesare disclosed.

According to Lederle, the esters and acids " . . . have potentialutility as hypotensive agents, anti-ulcer agents, agents for thetreatment of gastric hypersecretion and gastric erosion, agents toprovide protection against the ulcerogenic and other gastricdifficulties associated with the use of various non-steroidalantiinflammatory agents, bronchodilators, antimicrobial agents,anticonvulsants, abortifacients, agents for the induction of labor,agents for the induction of menses, fertility-controlling agents for theinduction of menses, fertility-controlling agents, central nervoussystem regulatory agents, salt and water-retention regulatory agents,diuretics, fat metabolic regulatory agents and as serum-cholesterollowering agents.

Biological data is presented for only six compounds of the numerousacids and esters disclosed. Anti-ulcer, gastric-antisecretory andbronchodilator properties are given for two 16-hydroxy prostaglandinanalogues (pp. 22-25): 9-oxo-16-hydroxyprostanoic acid and9-oxo-16-hydroxy-13-trans-prostenoic acid.

In summary, the two published Netherlands Patent Applications discussedabove disclose only prostaglandin analogues which are acids and esters.Of these analogues, only alkyl moieties and cycloalkyl moieties aredisclosed. In the latter class of compounds, the cycloalkyl is separatedfrom the C-16 position by interposition of at least one methylene group.The applications do not suggest that the claimed alkyl-substitutedcarbinols and the claimed cyclic and bicyclic carbinols and esters ofthe present invention would possess the unexpected separation ofbiological activity herein demonstrated.

SUMMARY OF THE INVENTION

The instant invention includes C₁₆ -hydroxy carbinol analogues of:

(a) prostaglandin E analogues having the structural formula: ##STR12##wherein: J is selected from the group consisting of R-hydroxymethyleneand S-hydroxymethylene;

R₁ is hydrogen;

R₂ is hydrogen or together with R₄ is a methylene chain of 2 to 3 carbonatoms such that a cycloalkyl of 5 to 6 carbon atoms inclusive is formed;

R₃ is selected from the group consisting of hydrogen or methyl, ortogether with R₄ is a methylene or a lower alkylated methylene chain of2 to 5 carbon atoms such that a cycloalkyl or a lower alkylatedcycloalkyl of 4 to 7 carbon atoms inclusive is formed, or together withR₄ is a bicycloalkyl or bicycloalkenyl moiety having the formula:##STR13## such that a bicycloalkyl or bicycloalkenyl compound is formed,wherein m and n are integers having a

value of from 0 to 3, p is an integer having a

value of from 0 to 4 and q is an integer having a

value of from 1 to 4 and wherein the double bond

of such bicycloalkenyl is in the m, n, p, or q bridge;

R₄ is hydrogen or methyl or together with R₂ or R₃ forms a cycloalkyl,bicycloalkyl or bicycloalkenyl as defined above, or together with R₅ isa methylene chain of 3 to 5 carbon atoms such that a cycloalkyl of 4 to6 carbon atoms inclusive is formed;

R₅ is selected from the group consisting of hydrogen, straight-chainalkyl having from 1 to B 3 carbon atoms or together with R₄ forms acycloalkyl as defined above; and

R₆ is selected from the group consisting of hydrogen or straight-chainalkyl having from 1 to 3 carbon atoms.

Included in this C₁₆ -hydroxy carbinol genus are the following subgeneraof prostaglandins;

(b) E₁ wherein R₁ and R₂ are hydrogen, R₃, R₄, R₅ and R₆ are selectedfrom the group consisting of hydrogen and straight-chain loweralkylhaving from 1 to 3 carbon atoms, having the structural formula IVb:##STR14##

(c) E₁ wherein R₂ and R₄ are closed to form a cycloalkyl having from 5to 6 carbon atoms inclusive;

(d) E₁ wherein R₂ is hydrogen and R₃ and R₄ are closed to form acycloalkyl or a lower alkylated cycloalkyl having from 4 to 7 carbonatoms inclusive;

(e) E₁ wherein R₂ is hydrogen and R₃ and R₄ are closed to form abicycloalkyl or bicycloalkenyl;

(f) a therapeutic method for inhibiting gastric secretion in anindividual for whom such therapy is indicated, comprising: administeringto the individual an effective gastric inhibiting amount of a compoundhaving the structural formula V: ##STR15## wherein: R₁ is hydrogen;

R₂ is hydrogen or together with R₄ is a methylene chain of 2 carbonatoms such that a cycloalkyl of 5 carbon atoms inclusive is formed;

R₃ is hydrogen or methyl, or together with R₄ is a methylene or a loweralkylated methylene chain of 2 carbon atoms, to form a loweralkylated-substituted cycloalkyl of 4 carbon atoms inclusive, ortogether with R₄ is a bicycloalkyl moiety having the formula: ##STR16##such that a bicycloalkyl compound is formed, wherein m and n areintegers having a value of 0, p is an integer having a value of 1 and qis an integer having a value of 2;

R₄ is hydrogen or methyl, or together with R₂ or R₃ forms a cycloalkyl,bicycloalkyl or bicycloalkenyl as defined above, with the proviso thatwhen R₅ is methyl, R₄ is hydrogen;

R₅ is hydrogen or methyl; and

R₆ is hydrogen or a straight-chain alkyl having 3 carbon atoms.

(g) a therapeutic method for producing bronchodilation in an individualfor whom such therapy is indicated, comprising: administering to theindividual an effective bronchodilating amount of a compound having thestructural formula V: ##STR17## wherein: J is selected from the groupconsisting of R-hydroxymethylene and S-hydroxymethylene;

R₁ and R₂ are hydrogen;

R₃ is selected from the group consisting of hydrogen and methyl, ortogether with R₄ is a methylene or a lower alkylated methylene chain of2 to 5 carbon atoms such that a cycloalkyl or a lower alkylatedcycloalkyl of 4 to 7 carbon atoms inclusive is formed, or together withR₄ is a bicycloalkyl or bicycloalkenyl moiety having the formula:##STR18## such that a bicycloalkyl or bicycloalkenyl compound is formed,wherein m and n are integers having a

value of from 0 to 3, p is an integer having a

value of from 1 to 4 and q is an integer having a

value of from 1 to 3 and wherein the double bond of such bicycloalkenylis in the m, n, p or q bridge;

R₄ together with R₃ forms a cycloalkyl or a lower alkylated cycloalkyl,bicycloalkyl or bicycloalkenyl as defined above, or together with R₅ isa methylene chain of 3 to 5 carbon atoms such that a cycloalkyl of 4 to6 carbon atoms inclusive is formed;

R₅ is selected from the group consisting of hydrogen, straight-chainalkyl having from 1 to 3 carbon atoms or together with R₄ forms acycloalkyl as defined above; and

R₆ is selected from the group consisting of hydrogen or straight-chainalkyl having from 1 to 3 carbon atoms.

(h) prostaglandin E analogues having the structural formula VI:##STR19## wherein: J is selected from the group consisting ofR-hydroxy-methylene and S-hydroxymethylene;

T is alkloxycarbonyl having from 1 to 2 carbon atoms inclusive in thealkyl group;

R₁ is hydrogen;

R₂ is hydrogen or together with R₄ is a methylene chain of 2 to 3 carbonatoms such that a cycloalkyl of 5 to 6 carbon atoms inclusive is formed;

R₃ is hydrogen or together with R₄ is a methylene or a lower alkylatedmethylene chain of 3 to 5 carbon atoms such that a cycloalkyl of 5 to 7carbon atoms inclusive is formed, or together with R₄ is a bicycloalkylor bicycloalkenyl moiety having the formula: ##STR20## such that abicycloalkyl or bicycloalkenyl compound is formed, wherein m and n areintegers having a

value of from 0 to 3, p is an integer having a

value of from 0 to 4 and q is an integer having a

value of from 1 to 3 and wherein the double bond of such bicycloalkenylis in the m, n, p or q bridge;

R₄ together with R₅ is a methylene chain of 3 to 5 carbon atoms suchthat a cycloalkyl of 4 to 6 carbon atoms inclusive is formed or togetherwith R₂ or R₃ forms a cycloalkyl, bicycloalkyl or bicycloalkenyl asdefined above; and

R₆ is hydrogen or a straight-chain alkyl of 1 to 3 carbon atoms.

Included in this C₁₆ -hydroxy alkoxy genus are the following subgeneraof prostaglandins;

(i) E₁ wherein R₁ is hydrogen and R₂ and R₄ are closed to form acycloalkyl having from 5 to 6 carbon atoms inclusive;

(j) E₁ wherein R₁ and R₂ are hydrogen and R₃ and R₄ are closed to form abicycloalkyl or bicycloalkenyl;

(k) E₁ wherein R₁ is hydrogen and R₃ and R₄ are closed to form acycloalkyl of 5 to 6 carbon atoms inclusive;

(l) E₁ wherein R₁ is hydrogen and R₄ and R₅ are closed to form acycloalkyl of 4 to 5 carbon atoms inclusive;

(m) a therapeutic method for producing bronchodilation in an individualfor whom such therapy is indicated, comprising: administering to theindividual an effective bronchodilating amount of a compound having thestructural formula VII: ##STR21## wherein: J is selected from the groupconsisting of R-hydroxymethylene and S-hydroxymethylene;

T is alkoxycarbonyl having from 1 to 2 carbon atoms inclusive in thealkyl group;

R₁ is hydrogen;

R₂ is hydrogen or together with R₄ is a methylene chain of 3 carbonatoms such that cycloalkyl of 6 carbons atoms inclusive is formed;

R₃ is hydrogen or together with R₄ is a methylene or a lower alkylatedmethylene chain of 4 carbon atoms such that a cycloalkyl of 6 carbonatoms inclusive is formed, or together with R₄ is a bicycloalkyl orbicycloalkenyl moiety having the formula: ##STR22## such that abicycloalkyl or bicycloalkenyl compound is formed, wherein m and n areintegers having a

value of from 0 to 3, p is an integer having a

value of from 0 to 4 and q is an integer having a

value of from 1 to 4, and wherein the double bond of such bicycloalkenylis in the m, n, p or q bridge;

R₄ is as defined above or together with R₅ is a methylene chain of 3 to4 carbon atoms such that cycloalkyl of 4 to 5 carbon atoms inclusive isformed; and

R₆ is H or a straight-chain alkyl of 1 to 3 carbon atoms;

(n) a therapeutic method for inhibiting gastric secretion in anindividual for whom such therapy is indicated, comprising: administeringto the individual an effective gastric inhibiting amount of a compoundwhich can be methyl11α,16RS-dihydroxy-16,20-methano-9-oxoprost-13E-en-1-oate; methyl11α,16RS-dihydroxy-16,18-methano-17,20-methano-9-oxoprosta-13E,19-dien-1-oate;methyl11α16RS-dihydroxy-16,18-methano-17,20-methano-9-oxoprost-13E-en-1-oateor methyl11α,16RS-dihydroxy-16,20-methano-17,20-methano-9-oxoprost-13E-en-1-oate;

(o) organolithiocuprates having the formula: ##STR23## wherein Ligrepresents a solubilizing ligand. Generally Lig is atri-(di-alkylamino)phosphine of 6-12 carbon atoms, trialkylphosphinehaving 3-12 carbon atoms, diarylphosphine, dialkylsulfide having 4-8carbon atoms, arylsulfide, or di-(trialkylsilyl)amino having 6-12 carbonatoms. Specifically Lig can be a tri(dimethylamino)phosphine,tri-(n-butyl)phosphine, diphenylphosphine, diisopropylsulfide,dibutylsulfide, phenylsulfide, or di-(trimethylsilyl)amino group.

R^(r) is iodide, thiophenylate, alkyn-1-yl having 3 to 8 carbon atoms orR^(t) ;

R^(t) is a radical having the formula: ##STR24## A is an acid-labilehydroxyl-protecting group, generally a tetrahydropyran-2-yl,trialkylsilyl, triarylsilyl, alkoxyalkyl having 2-6 carbon atoms, or atriarylmethyl group; and specifically is tetrahydropyran-2-yl,dimethyl(t-butyl)silyl, dimethylisopropylsilyl, trimethylsilyl,1-ethoxyethyl, ethoxymethyl, 1-methoxyethyl, methoxymethyl,2-ethoxyprop-2-yl, 2-methoxyprop-2-yl; or triphenylmethyl; wherein R₂and R₄ ; R₃ and R₄ and

R₄ and R₅ form a cycloalkyl as defined hereinbefore or

R₃ and R₄ form a bicycloalkyl or bicycloalkenyl as defined hereinbefore;and R₆ is as defined hereinbefore; and X is an integer of the set 1 to2.

(p) methods of preparing organolithiocuprates having the formula VII:##STR25##

(q) a method of synthesizing a prostaglandin analogue having thestructural formula VIII: ##STR26## wherein T is CH₂ OH, ##STR27## or##STR28## wherein R is a lower alkyl of 1 to 3 carbon atoms, by reactingan organolithiocuprate having the formula VII with a substituted2-cyclopenten-1-one having the structural formula IX: ##STR29## whereinT' is --CH₂ OA or ##STR30## to form an intermediate having thestructural formula X: ##STR31## hydrolyzing X with a weak acid to obtainthe prostaglandin; ##STR32## wherein T is CH₂ OH, ##STR33## or ##STR34##

(r) iodovinyl alcohols having the structural formula VIII: ##STR35##wherein R₂ and R₄, R₃ and R₄, or R₄ and R₅ form a cycloalkyl as definedhereinbefore or R₃ and R₄ form a bicycloalkyl or bicycloalkenyl asdefined hereinbefore;

(s) methods of preparing iodovinyl alcohols having the structuralformula VIII:

(t) protected-iodovinyl alcohols having the structural formula IX:##STR36##

(u) methods of preparing protected-iodovinyl alcohols having thestructural formula IX.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention, formula IV and VI, are preparedvia the 1,4-conjugate addition of a 2-cyclopenten-1-one and anorganolithiocuprate as reported by Sih, et. al., (J. Amer. Chem. Soc.,97: 857 and 865 [1975] and references cited therein). The reactionproceeds in a variety of inert solvent systems of which ether,tetrahydrofuran, hexane, pentane or toluene are representative. Theinert atmosphere can be provided by the use of argon or nitrogen. Theprostaglandin analogues of formula IV and VI are prepared according tothe reaction sequence depicted in Table A, described hereinafter.

                                      TABLE A                                     __________________________________________________________________________     ##STR37##                                                                     ##STR38##                                                                     ##STR39##                                                                    __________________________________________________________________________     ##STR40##                                                                

The reaction of the appropriate substituted 2-cyclopenten-1-one havingthe structural formula IX: ##STR41## with the organolithiocuprate offormula VII: ##STR42## in an inert solvent, under an inert atmosphere ata temperature of from -80° to +10° for about 0.25 to three hoursprovides the intermediate having the structural formula X: ##STR43##

Hydrolysis of the intermediate X provides compound XI. Chemicalhydrolysis can be accomplished by treatment with a weakly-acidic watermixture, e.g., acetic acid-water (65: 35 VV) with 10 percenttetrahydrofuran, at a temperature of about 20° to 45° C. for about 0.5to 48 hours.

All compounds of this invention can be isolated from reaction mixturesand purified and well-known organic chemistry procedures. For example,the compounds can be isolated by dilution of the reaction mixture withwater, extraction with a water-immiscible solvent such as benzene,cyclohexane, ether, ethyl acetate, methylene chloride, toluene and thelike; chromatography; distillation or a combination of these procedures.Purification of these compounds can be accomplished by methods which arewell-known in the art for the purification of prostaglandins, lipids,fatty acids, and fatty esters. Such methods as reverse phase partitionchromatography; counter-current distribution; adsorption chromatographyon acid washed magnesium silicate, neutral or acid washed silica gel,alumina or silicic acid; preparative paper chromatography; preparativethin layer chromatography; high pressure liquid-liquid chromatography;gas-liquid chromatography; and combinations thereof can be used topurify the compounds produced by the processes of this invention.

NMR spectra were determined in CDCl₃ and infrared (ir) spectra in CHCl₃unless otherwise noted. Analytical thin layer chromatography wasperformed on 0.2 mm Silica Gel 60 F254 plates and preparative thin-layerchromatography was performed using 2.0 mm Silica Gel 60 F254 plates."System II" is defined as the organic layer from a mixture of ethylacetate, acetic acid, isooctane, and water in a ratio of 11:2:5:10.Spots were visualized under uv light and/or by ceric sulfate sprayragent [See K. Schreiber, et al., J. Chromatography, 12, 63 (1962)].Column chromatographic separations were performed on 85: 15 silicicacid-diatomaceous earth, such as Celite, or silica gel 60 using abenzene-ethyl acetate or hexane-ethyl acetate gradient elution unlessotherwise specified. Mass spectra were determined by WARF, Inc.,Madison, Wis., or Morgan Schaffer, Inc., Montreal, Canada.

A. Preparation of Substituted 2-Cyclopenten-1-one

When T' of substituted 2-cyclopenten-1-one IX is ##STR44## thesubstituted 2-cyclopenten-1-one is prepared as described by Sih et al.,J. Amer. Chem. Soc., 97, 865 (1975).

When T' is --CH₂ OA, the substituted 2-cyclopenten-1-one is the natural"left-hand piece" described in Tetrahedron Letters, 2063 (1977)synthesized as outlined in Table B and summarized below.

Assymmetric, microbiological reduction of an appropriate2-(ω-hydroxyalkyl)-cyclopentane-1,3,4-trione XV provides thecorresponding 2-(ω-hydroxyalkyl)-4R-hydroxy-cyclopentan-1,3-dione XVI(Step A, Table B). The conversion of XV to XVI follows the proceduresdisclosed in U.S. Pat. No. 3,773,622 and utilizes microorganisms of theorders Endomycetales, Moliliales, and Eurotiliales in general andspecies Dipodascus uninucleatus and Dipodascus albidus in particular.Such microorganisms are in the public domain and can be obtained fromdepositories (American Tissue Type Collection [Bethesda, Md.] or theNational Regional Research Laboratory, U.S.D.A., [Peoria, Ill.]). Theadvantage of microbiological reduction to the C₄ carbonyl group of XV isthat it provides the chirality of the hydroxyl group requisite foranalogues of PGE₁. Chemical reduction on the other hand provides amixture of 2-(ω-hydroxyalkyl)-4RS-hydroxy-cyclopentane-1,3-diones.

Acylation or alkylation of XVI under alkaline conditions at atemperature of from -25° C. to 100° C. (step B, Table B) gives a mixtureof corresponding enol isomers, XVII and

                  TABLE B                                                         ______________________________________                                        Preparation of 2-cyclopent-en-1-ones XII                                      ______________________________________                                         ##STR45##                                                                     ##STR46##                                                                     ##STR47##                                                                     ##STR48##                                                                     ##STR49##                                                                     ##STR50##                                                                    ______________________________________                                    

XVIII. Acylating agents useful in that step are benzoyl chloride,mesitylenesulfonyl chloride, pivaloyl chloride, and acetyl chloride (1equivalent); alkylating agents include 2-iodopropane, 1-iodopropane,1-iodo-2-methylpropane, and 1-iodo-3-methylbutane. Symbol R' in each offormulas XVII and XVIII corresponds to the respective acyl or alkylgroup of the reagent utilized: benzoyl, mesitylenesulfonyl, pivaloyl,acetyl, prop-1-yl, 1-prop-2-yl, 2-methylprop-1-yl, and3-methyl-but-1-yl. Conditions for acylation or alkylation follow theteachings of the Sih reference (p. 866-867, and Table 1 on 867).

Separation of isomer XVII (step C, Table B), reduction with lithiumaluminum hydride, lithium borohydride or sodiumbis-(2-methoxyethoxy)aluminum hydride at a temperature of from -80° C.to +80° C. depending on the solvent utilized (step D1, Table B), andsubsequent removal of the acyl or alkyl group under acidic conditions ata temperature of from 20° C. to 35° C. (step D2, Table B) yields thecorresponding 2-(ω-hydroxylalkyl)-4R-hydroxy-2-cyclopenten-1-one, XIX.Conditions for those procedures again are disclosed in the Sih reference(p. 867).

Reaction of XIX with dihydropyran or an alkyl vinyl ether (methyl vinylether, ethyl vinyl ether, propyl vinyl ether) under acid-catalyzedconditions or with a trialkylsilyl chloride (trimethylsilyl chloride,t-butyldimethylsilyl chloride) or triphenylmethyl bromide under basicconditions and at room temperature (step E, Table B) provides asubstituted 2-cyclopenten-1-one IX in which the hydroxyl groups aremasked with a group A corresponding to the reagent utilized in thereaction.

The 2-(ω-hydroxylalkyl)-cyclopentane-1,3,4-triones XV are prepared fromketoalkanols having the formula ##STR51## in which m is an integer ofthe set 1-8 or preferably of the subset 4-6. Condensation of anappropriate ketoalkanol XX with a dialkyloxalate in a suitable solventand in the presence of an alkali metal base at reflux temperaturesprovides a 2-(ω-hydroxyalkyl)-5-(alkoxalyl)cyclopentane-1,3,4-trione ofthe formula, ##STR52## wherein and subsequently elsewhere G is an alkylgroup having 1-3 carbon atoms. The dialkyloxalate can be a dimethyl-, adiethyl-, or a dipropyl- oxalate of the general formula, (GO₂ C)₂.Methanol, ethanol, dimethoxymethane, or benzene serve as suitablesolvents for the reaction, and choice of solvent determines the refluxtemperature. Alkali metal bases useful in the above reaction include,among others: sodium metal, sodium hydride, sodium methoxide, sodiumethoxide, sodium propoxide, potassium t-butoxide, or lithium hydride.Treatment of XXI with heat, acid catalysis, heavy-metal salts (bariumhydroxide, manganese carbonate, calcium hydroxide, or thorium oxide), ordilute aqueous bases (NaHCO₃) removes the 5-alkoxalyl group to give thecorresponding 2-(ω-hydroxyalkyl)-cyclopentane-1,3,4-trione XV.

Ketoalkanols XX are prepared by two routes of synthesis. One utilizescertain alkyl ketoalkanoates as starting materials, the other certainalkane dienes.

The first synthetic pathway is schematically presented in Table C andexplained below.

Reaction of the appropriate compound XXII with a glycol of the formula,##STR53##

wherein and subsequently elsewhere, X is an oxygen or sulfur atoms, Q isa hydrogen atom or alkyl group having 1-2 carbon atoms and k is either 0or 1, under acid catalysis under reflux (e.g., p-toluene sulfonic acid)yields the corresponding alkyl ketoalkanoate-ketal, XXIV (step A, TableC). Reduction of XXIV with lithium aluminum hydride, lithiumborohydride, diisobutylaluminum hydride, sodiumbis-(2-methoxymethoxy)aluminum hydride, with an alkali-metal in liquidammonia (Bouveault-Blanc reaction), or by hydrogenating under pressurewith catalysis (Raney Nickel, Pd/C, Ag) gives the correspondingketoalkanol ketal XXV. Hydrolysis of the ketal group under acidicconditions at room temperature affords XX. Starting materials XXII arecommercially

                  TABLE C                                                         ______________________________________                                        Synthesis of Ketoalkanols XX From Alkyl Ketoalkanotes                         ______________________________________                                         ##STR54##                                                                     ##STR55##                                                                     ##STR56##                                                                     ##STR57##                                                                    ______________________________________                                    

                  TABLE D                                                         ______________________________________                                        Synthesis of Keotalkanols XX from Alkane Dienes                                ##STR58##                                                                     ##STR59##                                                                     ##STR60##                                                                     ##STR61##                                                                     ##STR62##                                                                     ##STR63##                                                                     ##STR64##                                                                    ______________________________________                                    

available or have been reported in the literature (Agr. Biol. Chem.[Japan], 33: 1079 [1969]). Compounds XXII are prepared by reactingmethyl cadmium with appropriate ω-alkoxycarbonyl-alkanoyl chlorides,which in turn are prepared from appropriate dicarboxylic acids or alkanedienes (J. Chem. Soc., 718 [1937]); J. Am. Chem. Soc., 68: 832 [1946]).Compounds XXI include 1,2-ethandiol, 1,2-propandiol, 1,3-propandiol,1,3-butandiol, 2,3-butandiol, 2,4-pentandiol, and 1,2-ethanedithiol.

Table D provides an outline of a second method of synthesizingketoalkanols XX.

Starting materials for the synthesis are alkane dienes XXVI such as1,4-pentadiene, 1,5-hexadiene, 1,6-heptadiene, 1,7-octadiene,1,8-nonadiene, 1,9-decadiene, 1,10-undecadiene, 1,11-dodecadiene. Suchdienes are commercially available or are prepared from correspondingdicarboxylic acids.

Reaction of XXVI with borane (less than 1 equivalent) in an inertsolvent followed by treatment with a peroxide (H₂ O₂ or acetic peroxide)in the presence of base and at a temperature of from -25° C. to +25° C.yields a corresponding alkenol XXVII (step A, Table D).

Oxidation of XXVII by known methods provides the alkenoic acid XXVII(step B, Table D). Any oxidizing means can be used in that step: Jonesreagent (J. Chem. Soc., 39 [1946]); silver(II)oxide; oxygen withplatinum catalyst; t-butyl chromate. Conditions of reaction will dependupon the selected means.

Reaction of XXVIII with methyllithium in an aprotic solvent at atemperature of from about -25° C. to +60° C. provides the ketoalkeneXXIX (step C, Table D). Alternately, XXVIII is converted to an alkenoylhalide. The alkenoyl halide is then reacted with methylmagnesiumchloride, dimethyl cadium or dimethyl zinc to give XXIX or is reactedwith the magnesium salt of dialkylmalonate (dimethyl, diethyl, ordipropyl malonate), hydrolyzed, and then decarboxylated to yield XXIX.

The carbonyl function of XXIX is protected by reacting the compound witha glycol XXIII (previously described) under acidic conditions and refluxto obtain the ketoalkene ketal, XXX (step D, Table D).

Reaction of XXX with borane and subsequently with peroxide in thepresence of base at a temperature of from -25° C. to +25° C. providesthe ketoalkanol ketal, XXXI (step E, Table D). Hydrolysis of the ketalto the corresponding ketoalkanol XX is performed under acidic conditionsand at room temperature (step F, Table D).

B. Preparation of Organolithiocuprates

The preparation of various organolithiocuprates used in the presentinvention is depicted in Table E below and described in detail followingTable E.

The organolithiocuprate utilized in the reaction is prepared in solutionprior to reaction with the 2-cyclopenten-1-one, and is represented byformula VII; ##STR65## The organolithiocuprate is prepared from theiodovinyl alcohol of structure XXXVII. In turn, the iodovinyl alcohol ofstructure XXXVII is prepared from the appropriate ketone or aldehydethrough an acetylenic alcohol intermediate. As depicted in Table E, theacetylenic alcohol intermediate can be prepared by alternate pathways.The acetylenic alcohol intermediate is then converted to thecorresponding iodovinyl alcohol. The hydroxyl function of the iodovinylalcohol is protected with an acid-labile hydroxy-protecting group.Alternately, the hydroxyl group of the acetylenic alcohol can beprotected prior to conversion of the alcohol to the correspondingiodovinyl compound.

The hydroxy-protected iodovinyl alcohol is then lithiated witht-butylithium and reacted with a solubilized Lig complex of a copper(I)compound such as (hexamethylphosphoroustriamide)₂ copper(I)pentyne toyield the desired organolithiocuprate.

                  TABLE E                                                         ______________________________________                                         ##STR66##                                                                     ##STR67##                                                                     ##STR68##                                                                     ##STR69##                                                                     ##STR70##                                                                     ##STR71##                                                                    ______________________________________                                    

Preparation of Iodovinylalcohol and Organolithiocuprate

As shown in Table E, the appropriate ketone XXXII was reacted with theappropriate acetylenic bromide XXXIII in the presence of magnesiummetal. The acetylenic alcohol XXXIV intermediate was recovered afterrefluxing the mixture. (See J. Amer. Chem. Soc., 93: 6967 [1971]).

Alternately, the acetylenic alcohol intermediate XXXIV can be preparedby reacting the appropriate alkene oxide XXXV with lithium acetylideethylene diamine complex XXXVI in hexamethylphosphoramide. (See Bio. 89:853 [1956]).

As shown in Table E, the acetylenic alcohol intermediate XXXIV can beconverted into the corresponding iodovinylalcohol XXXVII by adding tothe acetylenic alcohol diisobutylaluminum hydride in a solvent such asdry toluene followed by iodine in a solvent such as dry tetrahydrofuran(THF). (See J. Amer. Chem Soc., 97: 857 [1975]). The hydroxyl-group ofthe iodovinyl alcohol XXXVII is then protected by masking the hydroxylfunction with acid-catalyzed dihydropyran or ethyl vinyl ether orbasic-catalyzed trialkylsilyl chloride or triphenylmethyl bromide toobtain the protected alcohol XXXVIII. (See J. F. W. McOmie, "ProtectiveGroups in Organic Chemistry", Plenum Press, New York, 1973, p. 95f).

Alternately, the hydroxyl function of the acetylenic alcohol can beprotected as described above, and the protected alcohol converted intothe corresponding protected iodovinyl alcohol as taught in J. Amer.Chem. Soc., 94: 7827 (1972) and 83: 1241 (1961).

The iodovinyl alcohols have utility as intermediates in producing theprostaglandin analogues of the present invention.

The protected iodovinylalcohol is lithiated with metallic lithium or analkyllithium (n-butyl, sec-butyl or tert-butyl) to form the lithiocomplex XXXIX. The lithio complex XXXIX is reacted with the solubilizedcopper(I) species, for example, the hexamethylphosphorous trimidecomplex of copper n-propyl acetylide, to produce the desiredorganolithiocuprate XL. Specifically, (hexamethylphosphorous triamide)₂-copper(I)pentyne is disclosed in J. Amer. Chem. Soc., 94: 7211 (1972)and in J. Org. Chem., 31: 4071 (1966).Tri-n-butylphosphine-copper-(I)iodide is described in Inorg. Synth., 7:9 (1963). Hexamethylphosphorus triamide-copper(I)-iodide is taught inProstaglandins, 7: 38 (1974). Preparation of phenylthio-copper isdisclosed in Synthesis, 602 (1974). For a thorough review oforganolithiocuprates and their utility in the synthesis of naturalprostaglandins, see J. Amer. Chem. Soc., 97: 857 and 865 (1975). Theorganolithiocuprate is reacted with the desired substituted2-cyclopenten-1-one of formula IX as depicted in Table A.

The following Table F illustrates embodiments of the prostaglandinanalogues of the present invention compiled by Example No. and CompoundNo. and identified by the Chemical Abstracts system of nomenclature.

                  TABLE F                                                         ______________________________________                                        Example  Compound                                                             Number   Number    Chemical Abstracts Nomenclature                            ______________________________________                                        1        TR 4698   16-methyl-1, 11α, 16RS--                                                trihydroxyprsts-13E--en-9-one                              2        TR 4706   1, 11α, 16RS--trihydroxyprost-                                          13E-en-9-one                                               3a       TR 4752   1, 11α, 16R or S--trihydroxy-                                           17-dimethylprost-13E--en-9-                                                   one                                                        3b       TR 4751   1, 11α, 16R or S--trihydroxy-                                           17, 17-dimethylprost-13E--en-                                                 9-one                                                      4        TR 4749   1, 11α, 16RS--trihydroxy-17RS--                                         methylprost-13E--en-9-one                                  5a       TR 4848   15, 20-cyclo-1,11α,16S--                                                trihydroxy-prost-13E--en-                                                     9-one                                                      5b       TR 4840   15, 20-cyclo-1, 11α, 16R--                                              trihydroxy-prost-13E--en-                                                     13E--9-one                                                 6a       TR 4844   15, 19-cyclo-20-nor-1, 11α,                                             16R--trihydroxy-prost-                                                        en-9-one                                                   6b       TR 4846   15, 19-cyclo-20-nor-1,                                                        11α, 16S--trihydroxy-prost-                                             13E--en-9-one                                              7        TR 4703   16, 20-methano-1, 11α, 16-                                              trihydroxyprost-13E--en-9-one                              8        TR 4753   20-nor-16, 19-cyclo-1, 11α,                                             16-trihydroxyprost-13E--en-                                                   9-one                                                      9        TR 4851   16, 20-methano-18RS--methyl-1,                                                11α, 16RS--trihydroxyprost-                                             13E--en-9-one                                              10       TR 4770   16, 18-methano-1, 11α, 16RS--                                           trihydroxyprost-13E--en-9-one                              11       TR 4803   16, 18-methano-17, 20-methano-                                                1, 11α, 16RS--trihydroxyprosta-                                         13E, 19-dien-9-one                                         12a      TR 4804   16, 18-methano-17, 20-ethano-                                                 1, 11α, 16RS--trihydroxyprost-                                          13E--en-9-one                                              12b      TR 4806   16, 18-methano-17, 20-ethano-                                                 1, 16RS--dihydroxyprosta-10,                                                  13E--dien-9-one                                            13a      TR 4799   16, 18-methano-17, 20-methano-                                                1, 11α, 16RS--trihydroxyprost-                                          13E--en-9-one                                              13b      TR 4805   16, 18-methano-17, 20-methano-                                                1, 16RS--trihydroxyprosta-                                                    10, 13E--diene-9-one                                       14       TR 4903   16, 20-methano-17, 20-methano-1,                                              11α, 16RS--trihydroxyprost-                                             13E--en-9-one                                              15a      TR 4982   17, 20-methano-17-methyl-1,                                                   11α, 16R and S--trihydroxyprost-                                        13E--en-9-one                                              15b      TR 4983   17, 20-methano-17-methyl-1,                                                   11α, 16RS--trihydroxyprost-                                             13E--en-9-one                                              16a      TR 4984   17, 17-Propano-1, 11α, 16R--                                            trihydroxyprost-13E--en-9-one                              16b      TR 4985   17, 17-Propano-1, 11α, 16S--                                            trihydroxyprost-13E--en-9-one                              Comp. Proc.                                                                            TR 4704   Methyl 11α, 16RS--dihydroxy-                         A                  16-methyl-9-oxoprost-13E--oate                             Comp. Proc.                                                                            TR 4705   Methyl 11α, 16RS--dihydroxy-                         B                  9-oxoprost-13E--en-1-one                                   Comp. Proc.                                                                            TR 4836   Methyl 11α, 16R and S--dihydroxy-                    C                  17, 17-dimethyl-9-oxoprost-                                                   13E--en-1-oate                                             Comp. Proc.                                                                            TR 4814   Methyl 11α, 16RS--dihydroxy-                         D                  17-methyl-9-oxoprost-13E-oate                              17a      TR 4838   Methyl 15R, 19-cyclo-11α, 16-                                           trans-dihydroxy-20-nor-9-                                                     oxoprost-13E--en-1-oate                                    17b      TR 4839   Methyl 15S, 19-cyclo-11α, 16-                                           trans-dihydroxy-20-nor-9-                                                     oxoprost-13E--en-1-oate                                    18a      TR 4767   Methyl 15R, 20-cyclo-11α,                                               16-trans-dihydro-9-oxoprost-                                                  13E--en-1-oate                                             18b      TR 4768   Methyl 15S, 20-cyclo-11α,                                               16-trans-dihydro-9-oxoprost-                                                  13E--en-1-oate                                             19       TR 4717   Methyl 11α, 16RS--dihydroxy-16,                                         20-methano-9-oxoprost-                                                        13E--en-1-oate                                             20a      TR 4800   Methyl 11α, 16RS--dihydroxy-16,                                         18-methano-17, 20-methano-9-                                                  oxoprosta-13E, 19-dien-1-oate                              20b      TR 4802   Methyl 16RS--hydroxy-16, 18-                                                  methano-17, 20-methano-9-                                                     oxoprosta-10, 13E, 19-trien-                                                  1-oate                                                     21a      TR 4808   Methyl 11α, 16RS--dihydroxy-                                            17, 20-ethano-16, 18-methano-                                                 9-oxoprost-13E--en-1-oate                                  21b      TR 4807   Methyl 17, 20-ethano-16RS--                                                   hydroxy-16, 18-methano-9-                                                     oxoprosta-10, 13E--dien-1-oate                             22a      TR 4809   Methyl 11α, 16RS--dihydroxy-16,                                         18-methano-17, 20-methano-9-                                                  oxoprost-13E--en-1-oate                                    22b      TR 4801   Methyl 16RS--hydroxy-16, 18-                                                  methano-17, 20-methano-9-                                                     oxoprosta-10, 13E--dien-1-oate                             23       TR 4883   Methyl 11α, 16RS--dihydroxy-16,                                         20-methano-17, 20-methano-9-                                                  oxoprost-13E--en-1-oate                                    24a      TR 4978   Methyl 11α, 16R and S--                                                 dihydroxy-17, 17-propano-9-                                                   oxoprost-13E--ene-1-oate                                   24b      TR 4979   Methyl 11α, 16RS--dihydroxy-                                            9-oxo-17, 17-propanoprost-                                                    13E--en-1-oate                                             25a      TR 4980   Methyl 11α, 16R--dihydroxy-17,                                          20-methano-17-methyl-9-oxoprost-                                              13E--en-1-oate                                             25b      TR 4981   Methyl 11α, 16S--dihydroxy-17,                                          2-methano-17-methyl-9-oxoprost-                                               13E--en-1-oate                                             ______________________________________                                    

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 116-methyl-1,11α,16RS-trihydroxyprost-13E-en-9-one (TR4698)

The reaction pathway is shown below. ##STR72##

A. Preparation of Iodovinylalcohol [1-Iodo-4-methyloct-1E-en-4RS-ol]

A 12.2 g portion of magnesium turnings was heat dried under argon in a500 ml flask fitted with an air stirrer, condensor and addition funnel.After cooling the flask, 60 ml of dry ether was added, followed by asmall portion of a solution of 33.9 ml of propargyl bromide in 60 ml ofdry ether followed by 50 mg of mercuric chloride. After spontaneousether reflux indicated that the reaction had commenced, the remainder ofthe propargyl bromide solution was added dropwise to the mixture tomaintain gentle reflux. After the addition was complete, the reactionmixture was stirred for an additional one-half hour. A solution of 25 gof 2-hexanone, commercially available, in 25 ml of dry ether was thenadded to the reaction mixture, again at a rate to maintain gentlereflux. A heated oil bath was then used to reflux the final mixture foranother hour. The final mixture was then quenched by the addition ofwater, followed by 10 percent hydrochloric acid to dissolve solid salts.The phases were separated and the ether extract was washed with brineand saturated sodium bicarbonate solution. It was then dried over MgSO₄and then distilled using a water pump to successively remove ether and atrace of 2-hexanone (bp ca 30°). A 22.4 g portion (64 percent) of theacetylenic alcohol intermediate, methyloct-1-yn-4RS-ol, bp 70°-76° (ca20 mm) was recovered. Glc analysis of this product showed a 20 percentimpurity thought to be 4-methylocta-1,2-dien-4RS-ol. The distilled 80percent pure alcohol was used in successive experiments. The materialhad the following spectral characteristics: nmr (CDCl₃) δ 0.93 (3H,broad t, J=5 Hz), 1.0 to 1.7 (6H, m), 1.28 (3H, S), 1.82 (1H, s), 2.12(1H, t, J=3 Hz) and 2.39 ppm (2H, d, J=3 Hz), ir (CHCl₃) 1120, 1380,1460, 2120, (weak), 2870, 2930, 2960, 3300, 3200 to 3600 broad and 3590cm⁻¹.

The 4-methyloct-1-yn-4RS-ol was converted to the correspondingiodovinylalcohol, 1-Iodo-4-methyloct-1E-en-4RS-ol as described below.

A solution of 30 ml (169 mmol) of diisobutylaluminum hydride in 75 ml ofdry toluene was stirred under argon with ice water bath cooling as asecond solution of 7.0 g (50 mmol) of the 4-methyloct-1-yn-4RS-ol, in 25ml of dry toluene was added dropwise over a period of one hour. Stirringwas then continued without cooling for one hour and then with oil bathwarming (50°-60° C.) for three hours. The oil bath was then replacedwith a dry ice-acetone (-78° C.) bath as a third solution of 42.8 g (169mmol) of iodine in dry tetrahydrofuran to total 100 ml was addeddropwise to the reaction mixture maintaining a stirring of the reactionmixture. The cooling bath was then removed and the reaction mixture wasallowed to come to 20° slowly before it was quenched by being forcedunder a slight argon pressure through polyethylene tubing into avigorously stirred mixture of ether and two percent aqueous sulfuricacid. The ether phase was removed and then washed successively withanother portion of two percent sulfuric acid, brine, saturated aqueoussodium bicarbonate and brine. It was dried over Na₂ SO₄ and evaporatedunder reduced pressure. The residue (10.3 g) was chromatographed onsilica gel to yield 1.4 g of partially pure and 1.2 g of pure1-Iodo-4-methyloct-1E-en-4RS-ol, along with several grams of highlycontaminated material. The impure fractions were each distilled at 0.1mm to yield a total of 2.35 g of recovered acetylenic alcohol (bp50°-55° C.) and 2.55 g of reasonably pure iodovinylalcohol (bp 60°-65°C.). The total yield of pure iodovinylalcohol was thus 3.8 g: nmr(CDCl₃) δ 0.93 (3H, broad t, J=5 Hz), 1.18 (3H, s), 1.0-1.7 (6H, m),2.20 (1H, s), 2.25 (2H, d, J=7 Hz), 6.20 (1H, d, J=15 Hz) and 6.73 ppm(1H, d of t, J=15, 7 Hz); ir (film) 750, 900, 940, 1140, 1380, 1465,2870, 2930, 2960, and 3200-3600 cm⁻¹ (broad).

The conversion of the acetylenic alcohol can be carried out by replacingdiisobutylaluminum hydride with disiamylborane; a base, for example analkali metal hydroxide such as sodium or potassium hydroxide; atrialkylamine oxide such as trimethylamine oxide; and iodine.

B. Preparation of Organolithiocuprate from Iodovinylalcohol (1)Preparation of 1-Iodo-4-methyl-4RS-(tetrahydropyranyloxy)oct-1E-ene

The hydroxyl function of the iodovinylalcohol prepared as describedabove was protected as described below.

A solution of 0.806 g (3.00 mmol) of 1-iodo-4-methyloct-1E-en-4RS-ol,0.34 ml (3.73 mmol) of dihydropyran and a 5 mg portion oftoluenesulfonic acid in 1.5 ml of dry ether was stirred in a flask underargon. Tlc (CHCl₃, silica gel) analysis after one and one-half hoursindicated that the reaction was not completed; an additional 0.2 mlportion of dihydropyran and about 5 mg of toluene-sulfonic acid wereadded, followed after another hour with another 0.5 ml portion ofdihydropyran and toluenesulfonic acid. After a period of one andone-half hours, solid potassium carbonate was added to the reactionmixture. After stirring for several minutes the resultant mixture waswashed with water. The washed solution was back extracted with etherthree times. The combined extract was dried (Na₂ SO₄) and evaporated invacuo to yield 1.16 g of the title compound: nmr (CDCl₃) δ 0.95 (3H, m),1.20 (3H, s), 1.0-1.8 (12H, m), 2.3 (2H, d, J=8 Hz), 3.3-4.2 (2H, m),4.82 (1H, broad s), 6.12 (1H, d, J=14 Hz) and 6.73 ppm (1H, d of t,J=14, 7 Hz); ir (CHCl₃) 870, 950, 990, 1020, 1070, 1125, 1380, 1470,1610, 2870 and 2930 cm⁻¹.

(2) Preparation of Organolithiocuprate from Protected Iodovinylalcohol

A solution of 1.06 g (3.00 mmol) of 1-iodo-4-methyl-4RS(tetrahydropyranyloxy)-oct-1E-ene, in 10 ml of dry ether was stirred ina flask under argon with -78° bath cooling as 5.5 ml (6.00 mmol) of a1.18M solution of t-butyllithium in pentane was added dropwise viasyringe. The resultant solution was stirred at -78° for two hours.

A second solution was prepared by stirring under argon a suspension of0.392 g (3.00 mmol) of dry copper (I) pentyne in 5 ml of dry ethersolubilized with 1.10 ml of hexamethylphosphorus triamide, until itbecame homogeneous. This second solution was then transferred viasyringe to the above alkenyllithium reaction mixture as it was stirredwith -78° bath cooling. The desired lithiocuprate reagent, an orangemixture, was stirred 15 minutes after addition was complete.

C. Substituted 2-Cyclopenten-1-one

4R-(tetrahydropyran-2-yloxy)-2-[7-(tetrahydropyran-2-yloxy)heptyl]-2-cyclopenten-1-onewas prepared from the appropriate2-(ω-hydroxyalkyl)-cyclopenten-1,3,4-trione as described in TetrahedronLetters, 2063 (1977) and described in detail hereinbefore.

D. Prostaglandin Synthesis

The synthesis of the prostaglandin E₁ analogue was achieved as describedbelow.

A solution of 0.785 g (2.06 mmol) of4R-(tetrahydropyran-2-yloxy)-2-[7-(tetrahydropyran-2-yloxy)heptyl]cyclopent-2-enone,in 3 ml of dry ether was added dropwise to the lithiocuprate reactionmixture as stirring was continued at -78°. After addition was complete,the resultant orange mixture was stirred for 10 min. at -78° and then at-20° for three hours.

The reaction was quenched at -20° by the addition of sufficient twopercent aqueous sulfuric acid to give an acidic aqueous phase afterstirring. The resultant mixture was thoroughly shaken and then filteredthrough Celite. The filter pad was rinsed thoroughly with ether. Thefiltrate phases were separated and the organic phase was washed withbrine and saturated aqueous sodium bicarbonate. It was then dried overMgSO₄ and evaporated in vacuo to yield 1.5 g of residue containing thetetrahydropyran-protected form of TR 4698.

This residue was dissolved in 20 ml of acetic acid-water-tetrahydrofuran(65:35:10) and left to stand under argon for 41.5 hours at roomtemperature and the resultant solution evaporated in vacuo to remove thesolvent. The residue was dissolved in ethyl acetate and washed withsaturated aqueous sodium bicarbonate. The wash solution was backextracted with ethyl acetate. The combined extract was dried over MgSO₄and evaporated in vacuo to yield 1.29 g of a yellow residue. Thisresidue was chromatographed on silicic acid-diatomaceous earth (85:15)using benzene-ethyl acetate gradient elution to yield 193.1 mg (26.5percent) of the pure PGE₁ analogue along with less polar materials thatappeared to contain the PGE₁ analogue, and as a side-product, the PGAanalogue, both protected as tetrahydropyran-2-yl-ethers. These lesspolar materials were dissolved in another portion of aceticacid-water-tetrahydrofuran and left under argon for three days. Theproduct was isolated as earlier described, and the resultant residue waspurified by thin layer chromatography on silica gel (ether elution, 2 mmlayer) to yield 23.5 mg of the PGA side-product designated as TR 4702.No attempt was made to recover the small amount of additional PGE₁analogue which was also present. The spectral characteristics of TR 4698and the side-product PGA were:

TR 4698 [α]_(D) -58.6° (c 1.0, CHCl₃); R_(f) (system II) 0.29; nmr(CDCl₃) δ 0.93 (3H, m), 1.17 (3H, s), 1.0-2.7 (24H, m), 3.63 (5H, broads over broad t, J=6.0 Hz), 4.20 (1H, q, J=7.0 Hz) and 5.64 ppm (2H, m);ir (CHCl₃) 895, 970, 1065, 1150, 1740, 2860, 2930, and 3200-3600 cm⁻¹ ;ms (70 eV) 336 (p-H₂ O), 318 (p-2H₂ O), 278, 264, 253, 235, 217, 193.

TR 4702 [α]_(D) +70.7° (c 1.17, CHCl₃); R_(f) (ether) 0.19; nmr (CDCl₃)δ 0.96 (3H, m), 1.20 (3H, s)., 1.0-2.5 (23H, m), 3.37 (1H, m), 3.73 (2H,m), 5.73 (2H, m), 6.30 (1H, m) and 7.67 ppm (1H, m); ir (CHCl₃) 900,970, 1030, 1075, 1125, 1700, 2860, 2930, 3200-3600 and 3600 cm⁻¹ ; ms(70 eV) 321 (p-CH₃), 318 (p-H₂ O), 279, 261, 236, 218.

EXAMPLE 2 1,11α,16RS-trihydroxyprost-13E-en-9-one (TR 4706)

The method described in Example 1 was used to prepare TR 4706 byreplacing the 2-hexanone with commercially available pentanal. Theacetylenic alcohol intermediate, oct-1-yn-4RS-ol had the followingspectral characteristics: nmr (CDCl₃) δ 0.93 (3H, broad t, J=5 Hz), 1.0to 2.6 (10H, m) and 3.87 (1H, broad m); ir (CHCl₃) 925, 1210, 2420,2850, 2920, 2960, 3010, 3300, 3200 to 3600 (broad) and 3590 cm⁻¹.

The 1-iodooct-1E-en-4RS-ol had the following spectral characteristics:nmr (CDCl₃) δ 0.93 (3H, broad t, J=6 Hz), 1.0-1.7 (6H, m), 1.87 (1H, s),2.27 (2H, t, j=6 Hz), 3.77 (1H, broad m), 6.24 (1H, d, J=15 Hz) and 6.73ppm (1H, d of t, J=15, 6 Hz); ir (CHCl₃) 900, 950, 1470, 2860, 2930,2960, 3200-3600 (broad) and 3600 cm⁻¹.

The iodovinyl alcohol was protected to yield1-iodo-4RS-(tetrahydropyranyloxy)oct-1E-ene having the followingspectral characteristics: nmr (CDCl₃) δ 0.93 (3H, m), 1.0-2.8 (14H, m),3.3-4.2 (3H, m), 4.84 (1H, broad s), 6.20 (1H, d, J=14 Hz) and 6.73 ppm(1H, d of d, J=14, 7 Hz).

The resulting PGE₁ analogue had the following spectral characteristics:[α]_(D) -56.4° (o 1.0 CHCl₃); R_(f) (system II) 0.30; nmr (CDCl₃) δ 0.98(3H, m), 1.0-2.7 (24H, m); 3.75 (2H, broad t, J=6.0 Hz), 3.86 (3H, s),4.2 (2H, m), and 5.73 ppm (2H, m); ir (CHCl₃) 900, 970, 1070, 1110,1150, 1240, 1380, 1460, 1740, 2860, 2930, 3200-3600 and 3600 cm⁻¹ ; ms(70 eV) m/e 322 (p-H₂ O), 304 (p-2H₂ O), 254, 236.

EXAMPLE 3 1,11α,16R-trihydroxy-17,17-dimethylprost-13E-en-9-one and1,11α,16S-trihydroxy-17,17-dimethylprost-13E-en-9-one (TR4752 and TR4751)

A solution of 2,2-dimethylpentanal was substituted for the 2-hexanone ofExample 1. The 2,2-dimethylpentanal was produced from commerciallyavailable 2-methylpropionic acid as described below.

A 240 ml (285 mmol) portion of a solution of t-butyllithium in pentane(1.18M) was added dropwise to a solution of 42 ml (290 mmol) ofdiisopropylamine in 300 ml of dry tetrahydrofuran while it was stirredwith -5° bath cooling under argon. A 12.7 ml (135 mmol) portion of2-methylpropionic acid in 15 ml of dry tetrahydrofuran was then addeddropwise to the reaction mixture. A 14.3 ml (140 mmol) portion ofn-propyliodide was then added dropwise to the reaction mixture asstirring was continued with ice bath cooling. The resultant mixture wasstirred two hours without cooling and then acidified by the slowaddition of 10% hydrochloric acid. The resultant mixture was extractedseveral times with ether and the combined extracts were washed withbrine, dried (Na₂ SO₄) and evaporated in vacuo to yield 16.3 g of2,2-dimethylpentanoic acid, having the following spectralcharacteristics: nmr (CDl₃) δ 0.94 (3H, t, J=8.5 Hz), 1.20 (6H, s),1.2-1.8 (4H, m) and 11.3 ppm (1H, broad s); ir (CHCl₃) 860, 945, 1185,1240, 1290, 1310, 1370, 1410, 1480, 1700 and 2400-3400 cm⁻¹ (broad).

The 2,2-dimethylpentanoic acid was converted to 2,2-dimethylpentanol asdescribed below.

A solution of 16.3 g (125 mmol) of 2,2-dimethylpentanoic acid in 10 mlof dry ether was added dropwise to a stirred slurry of 7.11 g (187 mmol)of lithium aluminum hydride in 250 ml of dry ether, under argon. Afteraddition was complete, the resultant mixture was refluxed for threehours. It was then cooled with an ice bath and excess hydride wasdestroyed by the dropwise addition of 10 ml of ethyl acetate. This wasfollowed by the careful dropwise addition, with vigorous stirring, of 8ml of water, 8 ml of 15 percent aqeous sodium hydroxide and 16 ml ofwater, sequentially. The resultant mixture was stirred several minutesuntil the solid had turned uniformly white. It was then filtered througha diatomaceous earth filter. The filter pad was rinsed thoroughly withether. The combined filtrate was evaporated in vacuo to yield 11.3 g.The pentanol had the following spectral characteristics: nmr (CDCl₃) δ0.87 (9H, broad s), 1.0-1.5 (4H, m), 2.3 (1H, broad s) and 3.36 ppm (2H,broad s); ir (CHCl₃) 655, 730, 900, 1030, 1205, 1360, 1470, 2880, 2950,3200-3600 (broad) and 3600 cm⁻¹.

A solution of 1.0 g (10 mmol) of 2,2-dimethylpentanol in 3 ml ofmethylene chloride was added rapidly to a stirred suspension of 4.0 g ofpyridinium chlorochromate in 20 ml of methylene chloride under argon. Ablack gum quickly settled from the reaction mixture. The resultantmixture was stirred for two hours. It was then diluted with ether andthe supernatant was decanted. The residue left in the reaction flask wasextracted four more times with ether. The combined decanted extractswere filtered and evaporated. The yield of 2,2-dimethylpentanal was 0.9g.

The process was repeated on a larger scale using 9.5 g of2,2-dimethylpentanol with 40 g of pyridinium chlorochromate in a totalof 130 ml of methylene chloride to yield 9.7 g of 2,2-dimethylpentanal:nmr (CDCl₃) δ 9.67 (1H, S), 1.04 (6H, S) and 0.8 to 1.6 ppm (7H, m); ir(CHCl₃) 905, 1230, 1365, 1470, 1725, 2720, 2880, and 2970 cm⁻¹.

The 2,2-dimethylpentanal was substituted for the 2-hexanone ofExample 1. The procedure of Example 1 was followed to obtain thecorresponding acetylenic alcohol, the corresponding iodovinyl alcoholand the corresponding hydroxyl-protected iodovinyl alcohol. Theacetylenic alcohol, 5,5-dimethyloct-1-yn-4RS-ol, had the followingspectral characteristics: nmr (CDCl₃) δ 0.90 (6H, s), 0.8-1.6 (7H, m),2.08 (1H, t, J=2.7 Hz), 2.38 (2H, m), 2.28 (1H, broad s) and 3.60 ppm(1H, d of d, J=5.0, 9.0 Hz); ir (CHCl₃) 860, 1030, 1365, 1470, 2100(weak), 2860, 2950, 3300, 3200-3600 (broad) and 3580 cm⁻¹.

1-Iodo-5,5-dimethyloct-1E-en-4RS-ol had the following spectralcharacteristics: nmr (CDCl₃) δ 0.88 (9H, broad s), 1.0-2.0 (5H, m), 2.23(2H, m), 3.4 (1H, m), 6.17 (1H, d, J=15 Hz) and 6.72 ppm (1H, d of t,J=15, 7 HZ); ir (CHCl₃) 945, 1050, 1365, 1470, 1610, 2860, 2930, 2970,3200-3600 (broad) and 3600 cm⁻¹.

1-Iodo-5,5-dimethyl-4RS-(tetrahydropyranyloxy)oct-1E-ene had thefollowing spectral characteristics: nmr (CDCl₃) δ 0.9 (9H, broad s),1.0-2.0 (10H, m), 2.25 (2H, m), 3.2-4.2 (3H, m), 4.50 (1H, broad s),6.02 (1H, d, J=14 Hz), and 6.3-7.0 (1H, m); ir (CHCl₃) 1020, 1070, 1130,1380, 2860 and 2950 cm⁻¹.

As described in Example 1, the organolithiocuprate was prepared from thetetrahydropyranyloxy-protected iodovinyl alcohol and reacted with4R-(tetrahydropyran-2-yloxy)-2-[7-tetrahydropyran-2-yloxy)heptyl]cyclopent-2-enoneto produce the following PGE₁ analogue isomers, TR 4751 and 4752. Theisomers were separated by chromatographic procedures.

TR 4752 Polar Isomer-[α]_(D) -78.7° (c 1.11, CHCl₃); R_(f) (system II)0.40; nmr (CDCl₃) δ 0.83 (9H, broad s), 1.0-3.1 (21H , m), 3.1-4.3 (7H,m) and 5.48 ppm (2H, m); ir (CHCl₃) 970, 1080, 1160, 1240, 1740, 2860,2940, and 3100-3600 cm⁻¹ ; ms (70 eV) m/e 368 (p), 350, 332, 317, 307,283, 265, 254, 236.

TR 4741 Less Polar Isomer-[α]_(D) -37.0° (c 1.01, CHCl₃); R_(f) (systemII) 0.41; nmr, ir and ms are essentially the same as those for the polarisomer above.

EXAMPLE 4 1,11α,16RS-trihydroxy-17RS-methylprost-13E-en-9-one (TR 4749).

A solution of 2RS-methylpentanal was substituted for the2,2-dimethylpentanal of Example 3. The 2RS-methylpentanal was producedas described in Example 3 by replacing 2,2-dimethylpentanoic acid withcommercially available 2-methylvaleryl chloride and converting thechloride into 2-methylpentanol. The 2-methylpentanol had the followingspectral characteristics: nmr (CDCl₃) δ 0.92 (6H, m), 1.0-2.l0 (5H, m),2.87 (1H, broad s) and 3.48 ppm (2H, d, J=5.5 Hz); ir (CHCl₃) 980, 1020,1245, 1385, 1465, 2870, 2930, 2970, 3200-3600 (broad) and 3600 cm⁻¹.

The 2-methylpentanol was converted to 2RS-methylpentanal as described inExample 3. The product had the following spectral characteristics: nmr(CDCl₃) δ 9.83 (1H, d, J=2 Hz) and 0.8-1.8 ppm (11H, m); ir (CHCl₃) 900,1040, 1105, 1720, 2870, 2930 and 2970 cm⁻¹.

The 5RS-methyloct-1-yn-4RS-ol had the following spectralcharacteristics: nmr (CDCl₃) δ 0.8-1.8 (11H, m), 2.08 (1H, t, J=3.0 Hz),2.22 (1H, broad s), 2.40 (2H, d of d, J=3.0, 6.0 Hz) and 3.66 ppm (1H,m); ir (CHCl₃) 905, 1040, 1385, 1460, 2120 (weak), 2880, 2930, 2970,3310 3220-3600 (broad) and 3600 cm⁻¹.

The acetylenic alcohol was converted to the corresponding iodovinylalcohol, 1-iodo-5RS-methyloct-1E-en-4RS-ol and the hydroxyl-protectediodovinyl alcohol as described in Example 1. The iodovinyl alcohol hadthe following spectral characteristics: nmr (CDCl₃) 0.90 (6H, m),1.0-2.0 (6H, m), 2.20 (2H, t, J=14 Hz) and 6.58 (1H, d of t, J=14, 7Hz); ir (CHCl₃) 905, 950, 1205, 1385, 1460, 1612, 2880, 2940, 2960,3200-3600 (broad) and 3600 cm⁻¹.

1-iodo-5RS-methyl-4RS-(tetrahydropyranyloxy)oct-1E-ene had the followingspectral characteristics: nmr (CDCl₃) δ 0.9 (6H, m), 1.0-2.5 (13H, m),3.3-4.2 (3H, m), 4.60 (1H, broad s), 6.06 (1H, d, J=14 Hz) and 6.53 ppm(1H, d of t, J=14, 7 Hz).

As described in Example 1, the organolithiocuprate was prepared from thetetrahydropyranyloxy-protected iodovinyl alcohol and reacted with the2-cyclopenten-1-one of Example 1 to produce TR 4749 having the followingspectral characteristics: [α]_(D) -62.4° (c 1.04, CHCl₃); R_(f) (systemII) 0.29; nmr (CDCl₃) δ 0.93 (6H, m), 1.0-3.0 (23H, m), 3.3-4.3 (7H, m)and 5.52 ppm (2H, m); ir (CHCl₃) 970, 1070, 1160, 1240, 1380, 1460,1740, 2860, 2940, and 3100-3600 cm⁻¹ ; ms (70 eV) m/e 354 (p) 336, 318,307, 231, 218.

Compounds of the present invention were prepared wherein R₂ and R₃ areclosed to form cycloalkyl having from 5 to 6 carbon atoms inclusive andwherein R₃ and R₄ are closed to form cycloalkyl having from 4 to 8carbon atoms inclusive. Example 5 describes the preparation of an R₂ andR₃ ring-closed compound from a cycloalkene oxide as indicated in TableE.

EXAMPLE 5 15,20-Cyclo-1,11α,16S-trihydroxy-prost-13E-en-9-one and15,20-Cyclo-1,11α,16S-trihydroxy-prost-13E-en-9-one (TR 4848 and TR4840)

A solution of 4.0 g of commercially available cyclohexene oxide and 41ml of hexamethylphosphoramide (HMPA) was stirred under argon at 25°.Commercially available lithium acetylide ethylene diamine complex (9.65g) was added and the reaction mixture heated at 80° for two hours. Thereaction mixture was cooled to 0° and 20 percent aqueous ammoniumchloride added. The mixture was extracted with ether. The extracts werewashed with 10 percent HCl, water (five times), saturated aqueous NaHCO₃and brine, then dried, filtered, and distilled using aspirator vacuum toyield 2.98 g of (±)-trans-2-ethynylcyclohexanol, bp 73°-75°. The producthad the following spectral characteristics: nmr (CDCl₃) δ 0.8-2.5 (10H,m), 2.58 (1H, broad s) and 3.55 (1H, broad m); ir (CHCl₃) 840, 1010,1070, 1110, 1270, 1450, 2110, 2860, 2950, 3300, 3200-3600 (broad) and3575 cm⁻¹.

The acetylenic alcohol was converted into the corresponding iodovinylalcohol and protected iodovinyl alcohol as described in Example 1. The4-methyloct-1-yn-4RS-ol of Example 1 was replaced withtrans-2-ethynylcyclohexan-1RS-ol; the following change was made in theprocedure. When the iodine solution was added to the reaction mixture,it was added only until color persisted for one minute or more. Productisolation proceeded as in Example 1. The resultant product,trans-2-(2E-iodoethenyl) cyclohexan-1RS-oil had the following spectralcharacteristics: nmr (CDCl₃) 0.8-2.3 (10H, m), 3.3 (1H, broad m), 6.13(1H, d, J=14 Hz) and 6.50 Hz (1H, d of d, J=14, 7 Hz).

The tetrahydropyranyloxy-protected iodovinyl alcohol,trans-2-(2E-iodoethenyl)-1RS-(tetrahydropyranyloxy)cyclohexane, had thefollowing spectral chracteristics: nmr (CDCl₃) δ 0.8-2.2 (15H, m),3.2-4.2 (3H, M), 4.5 (1H, broad s), 6.02 (1H, d, J=14 Hz) and 6.53 ppm(1H, d of t, J=14, 7 Hz); ir (CHCl₃) 860, 900, 980, 1020, 1075, 1120,1360, 1450, 1610, 2850, and 2950 cm⁻¹.

The synthesis of the PGE₁ analogue was carried out as described inExample 1. Chromatography of the crude product yielded15S,20-cyclo-1,11α,16R-trihydroxyprost-13E-en-9-one and15R,20-cyclo-1,11α,16S-trihydroxyprost-13E-en-9-one. The physicalcharacteristics of the isomers were:

Less polar-R_(f) (system II) 0.38 nmr (CDCl₃) δ 0.9-2.5 (23H, complex),2.28 (3H, broad s), 3.62 (2H, broad t), 3.2-4.2 (2H, complex) and 5.57(2H, m); ir (CHCl₃) 970, 1460, 1740, 3200-3600 and 3600 cm⁻¹ ; ms (70eV) m/e 338, 320, 302, 389.

More polar-[α]_(D) -70.5° (c 0.54, CHCl₃); R_(f) (system II) 0.33 nmr(CDCl₃) δ 0.9-2.5 (23H, complex), 2.8-4.2 (5H, complex), 3.6 (2H, broadt) and 5.42 ppm (2H, m); ir (CHCl₃) 970, 1450, 1740, 3200-3600 adn 3600cm⁻¹ ; ms as above for the less polar isomer.

EXAMPLE 6 15,19-cyclo-20-nor-1,11α,16R-trihydroxy-prost-13E-en-9-one and15,19-cyclo-20-nor-1,11α,16S-trihydroxy-prost-13E-en-9-one (TR 4844 andTR 4846)

The cyclohexene oxide of Example 5 was replaced with commerciallyavailable cyclopentene oxide. The procedure of Example 5 was followed toconvert the cyclopentene oxide into the corresponding acetylenicalcohol, trans-2-ethynylcyclopentan-1RS-ol. The acetylenic alcohol hadthe following spectral characteristics: bp 72° (20 mm); nmr (CDCl₃) δ1.0 to 3.0 (9H, m) and 4.25 ppm (1H, m); ir (CHCl₃) 860, 900, 995, 1080,1215, 1450, 2110, 2860, 2960, 3300, 3200-3600 (broad) and 3600 cm⁻¹.

The procedure of Example 5 was followed to obtain the correspondingiodovinyl alcohol and the corresponding protected iodovinyl alcohol byreplacing trans-2-ethynylcyclohexan-1RS-ol withtrans-2-ethynylcyclopentan-1RS-ol. The iodovinyl alcohol,trans-2-(2E-iodoethenyl)-cyclopentan-1RS-ol had the spectralcharacteristics: nmr (CDCl₃) δ 0.8-2.7 (8H, m), 3.85 (1H, broad m), 6.10(1H, d, J=14 Hz) and 6.50 (1H, d of d, J=14, 7 Hz); ir (CHCl₃) 870, 910,960, 1040, 1080, 2870, 2940, 3200-3600 (broad) and 3580 cm⁻¹.

The trans-2-(2E-iodoethenyl)-1RS-(tetrahydropyranyloxy)cyclopentane hadthe following spectral characteristics: nmr (CDCl₃) δ 0.8-2.3 (13H, m)3.2-4.2 (3H, m), 4.65 (1H, broad s), and 5.9 to 6.8 ppm (2H, m); ir(CHCl₃) 865, 910, 975, 1030, 1075, 1130, 2880 and 2960 cm⁻¹.

The synthesis of the PGE₁ analogue was carried out as described inExample 1. Chromatography of the crude product yielded the two isomersreferred to earlier. The isomers had the following spectralcharacteristics:

Less polar-[α]_(D) -22.9° (c 0.65, CHCl₃); R_(f) (System II) 0.24 nmr(CHCl₃) δ 1.0-2.4 (23H, complex), 2.82 (3H, broad s), 3.6 (2H, broad t),3.3-4.2 (2H, complex) and 5.57 ppm (2H, m); ir (CHCl₃) 970, 1460, 1740,3200-3600 and 3600 cm⁻¹ ; ms (70 eV) m/e 324, 306, 288, 278, 236.

More polar-[α]_(D) -65.9° (c 0.61, CHCl₃); R_(f) (system II) 0.20 nmr(CDCl₃) δ 0.9-2.5 (23H, complex), 2.7-4.2 (7H, complex) and 5.52 (2H,m); ir (CHCl₃) 970, 1460, 1740, 3200-3600 and 3600 cm⁻¹ ; ms as abovefor the less polar isomer.

The following R₃ and R₄ ring-closed compounds wherein R₃ and R₄ form acycloalkyl having from 4 to 8 carbon atoms inclusive, were prepared asdescribed in Example 1.

EXAMPLE 7 16,20-Methano-1,11α,16-trihydroxyprost-13E-en-9-one (TR 4703)

A solution of commercially available cyclohexanone was substituted forthe 2-hexanone of Eample 1. The procedure of Example 1 was followed toobtain the corresponding acetylenic alcohol, the corresponding iodovinylalcohol and the corresponding hydroxyl-protected iodovinyl alcohol. Theacetylenic alcohol, 1-(prop-2-ynyl)cyclohexanol, had the followingspectral characteristics: nmr (CDCl₃) δ 1.0-2.0 (10H, m), 2.0-2.2 (2H,m) and 2.39 ppm (2H, m); ir (CHCl₃) 870, 980, 1060, 1150, 1270, 1450,2120 (weak), 2860, 2930, 3300, 3200-3600 (broad) and 3570 cm⁻¹.

The cyclohexanol was converted into the corresponding iodovinyl alcoholby replacing 4-methyloct-1-yn-4RS-ol with 1-(prop-2-ynyl)cyclohexanol.The yield was low (0.54 g from 7.0 g of the hexanol). An alternateprocedure, described below, was devised to prepare additional amounts ofthe iodovinyl alcohol and corresponding protected iodovinyl alcohol from1-(prop-2-ynyl)cyclohexanol.

A solution of 2.9 g (21 mmol) of (prop-2-ynyl)cyclohexanol in 10 ml ofdry ether was stirred under argon as 0.24 ml (26 mmol) of dihydropyranwas added followed by about 5 mg of toluenesulfonic acid. After onehour, tlc (CHCl₃, silica gel) analysis indicated that significantstarting material remained. Another 0.2 ml of dihydropyran and about 5mg of toluenesulfonic acid were added. Twice more at one hour intervals,0.2 ml portions of dihydropyran along with a small amount oftoluenesulfonic acid were added to the reaction mixture. It was left tostir under argon at room temperature for 15 hours. Potassium carbonatewas then added to the mixture and it was stirred for several minutesbefore it was washed with water. The wash solution was back extractedwith ether and the combined extracts were then washed with brine, dried(Na₂ SO₄) and evaporated in vacuo to yield 4.6 g of1-(tetrahydropyran-2-yloxy)-1-(prop-2-ynyl)cyclohexane) having thefollowing spectral characteristics: nmr (CDCl₃) δ 1.0-2.5 (19H, m), 3.6(2H, broad m) and 4.65 ppm (1H, broad s); ir (CHCl₃) 980, 1030, 1050,1070, 1120, 1150, 1270, 1450, 2120, (weak) 2760, 2930 and 3300 cm⁻¹.

A 200 ml portion of 1M borane in tetrahydrofuran was stirred under argonwith -10° bath cooling in a flask fitted with a dry ice condensor. Atotal of 46 ml (400 mmol) of 2-methyl-2-butene was then added slowly viasyringe below the surface of the borane solution. The reaction mixturewas then stirred one hour at 0° and then left overnight in arefrigerator.

A 10 ml portion of the above disiamylborane solution was stirred underargon with ice bath cooling as 2.4 g of1-(tetrahydropyran-2-yloxy)-1-(prop-2-ynyl)-cyclohexane, was addedslowly. The resultant solution was stirred at room temperature for twohours. Tlc (CHCl₃, silica gel) showed that the reaction was notcomplete. A second 10 ml portion of disiamylborane solution was added tothe reaction mixture. After another 1.5 hour the reaction was quenchedby the addition of 3.3 g of trimethylamine oxide dihydrate portionwiseover 30 minutes. The resultant mixtue was stirred at 0° for one hour. A33 ml portion of 1M aqueous sodium hydroxide was then added, quicklyfollowed by a solution of 7.6 g of iodine in 40 ml of drytetrahydrofuran. The resultant mixture was stirred one hour without acooling bath and then poured into 100 ml of water. Sodium thiosulfatewas then added until the color of excess iodine had dissipated. Theresultant mixture was extracted with ether. The extract was washed withwater and then brine. It was evaporated in vacuo to yield 9.00 g ofresidue. This residue was dissolved in methanol and benzene which werethen removed by evaporation in vacuo to yield 5.0 g of residue. Thisresidue was chromatographed on silica gel using chloroform elution toyield 2.4 g of pure material.

The 1-(3-idoprop-2E-enyl)-1-(tetrahydropyranyloxy)-cyclohexane had thefollowing spectral characteristics: nmr (CDCl₃) δ 0.90 (3H, m), 1.0-2.0(16H, m), 2.35 (2H, d, J=8 Hz), 3.3-4.3 (2H, m), 4.83 (1H, broad s),6.09 (1H, d, J=14 Hz) and 6.77 ppm (1H, d of t, J=14, 7 Hz); ir (CHCl₃)960, 990, 1030, 1075, 1125, 1460, 1610, 2870 cm⁻¹.

The synthesis of the PGE₁ analogue was carried out as described inExample 1. The prostaglandin analogue had the following spectralcharacteristics: [α]_(D) -55.5° (c 1.0, CHCl₃); R_(f) (system II) 0.22;nmr (CDCl₃) δ 1.0-2.8 (29H, m), 2.99 (3H, broad s), 3.73 (2H, t, J=6.0Hz), 4.17 (1H, m) and 5.70 ppm (2H, m); (CHCl₃) 910, 970, 1070, 1150,1240, 1340, 1380, 1450, 1740 2860, 2930 and 3200-3600 cm⁻¹ ; ms (70 eV)m/e 334 (p-H₂ O), 262, 253, 235, 217.

EXAMPLE 8 20-Nor-16,19-cyclo-1,11α,16-trihydroxyprost-13E-en-9-one (TR4753)

A solution of commercially available cyclobutanone was substituted forthe 2-hexanone of Example 1. The procedure of Example 1 was followed toobtain the corresponding acetylenic alcohol, the corresponding iodovinylalcohol, and the corresponding hydroxyl-protected iodovinyl alcohol. Theacetylenic alcohol, 1-(prop-2-ynyl) cyclobutanol, had the followingspectral characteristics: bp 60-62) (20 mm); nmr (CDCl₃) complex m at δ0.8-2.5 ppm; ir (CHCl₃) 850, 1060, 1130, 1250, 1370, 1455, 2240, 2860,2930, 2970, 3300, 3200-3600 (broad) and 3600 cm⁻¹.

The acetylenic alcohol was converted into the corresponding iodovinylalcohol and the corresponding protected iodovinyl alcohol by replacing4-methyloct-1-yn-4RS-ol with 1-(prop-2-ynyl) cyclobutanol. The1-(3-iodoprop-2E-enyl) cyclobutanol had the following spectralcharacteristics: nmr (CDCl₃) δ 1.0-2.5 (9H, m), 6.12 (1H, d, J=14 Hz)and 6.60 ppm (1H, d of t, J=14, 7 Hz).

The 1-(3-iodoprop-2E-enyl)-1-(tetrahydropyranyloxy) cyclobutane had thefollowing spectral characteristics: nmr (CDCl₃) δ 1.2-2.3 (13H, m), 2.4(2H, d, J=7 Hz), 3.3-4.2 (2H, m), 4.70 (1H, broad s), 6.08 (1H, s, J=14Hz) and 6.63 ppm (1H, d of t, J=14, 7 Hz); ir (CHCl₃) 860, 980, 1020,1070, 1120, 1275, 1440, 1610, 2850, 2940 cm⁻¹.

The synthesis of the PGE₁ analogue was carried out as described inExample 1. The prostaglandin analogue had the following spectralcharacteristics: [α]_(D) -37.1° (c 0.97, CHCl₃); R_(f) (system II) 0.16;nmr (CDCl₃) δ 0.8-2.7 (24H, m), 3.2-4.3 (6H, m) and 5.57 ppm (2H, m); ir(CHCl₃) 970, 1020, 1075, 1160, 1220, 1265, 1345, 1440, 1740, 2860, 2930,and 3100-3600 cm⁻¹ ; ms (70 eV) m/e 306 (p-H₂ O), 278, 236.

EXAMPLE 916,20-Methano-18RS-methyl-1,11α,16RS-trihydroxyprost-13E-en-9-one (TR4851)

A solution of commercially available 3RS-methylcyclohexanone wassubstituted for the 2-hexanone of Example 1. The procedure of Example 1was followed to obtain the corresponding acetylenic alcohol, thecorresponding iodovinyl alcohol and the corresponding hydroxyl-protectediodovinyl alcohol. The acetylenic alcohol,3RS-methyl-1RS-(prop-2-ynyl)cyclohexanol, had the following spectralcharacteristics: nmr (CDCl₃) δ 0.88 (3H, d, J=6 Hz), 1.0-2.0 (10H, m),2.07 (1H, t, J=2.5 Hz) and 2.32 ppm (2H, d, J=2.5 Hz); ir (CHCl₃) 950,1000, 1100, 1165, 1260, 1380, 1450, 2110 (weak), 2860, 2930, 3300,3200-3600 (broad) and 3570 cm⁻¹.

The acetylenic alcohol was converted into the corresponding iodovinylalcohol and the corresponding protected iodovinyl alcohol by replacingthe 4methyloct-1-yn-4-RS-ol with the above3RS-methyl-1RS-(prop-2-ynyl)cyclohexanol. The resultant product,1RS-(3-iodoprop-2E-enyl)-3RS-methylcyclohexanol had the followingspectral characteristics: (CDCl₃) δ 0.90 (3H, d, J=6 Hz) 1.0-1.9 (10H,m), 2.18 (2H, d, J=7 Hz), 6.10 (1H, d, 7=14 Hz) and 6.65 ppm (1H, d oft, J=14, 7 Hz); ir (CHCl₃) 945, 995, 1155, 1380, 1450, 1608, 2860, 2930,3200-3600 (broad) and 3600 cm⁻¹.

The1RS-(3-iodoprop-2E-enyl)-3RS-methyl-1RS-(tetrahydropyranyloxy)cyclohexanehad the following spectral characteristics: nmr (CDCl₃) δ 0.86 (3H,broad d, J=5.5 Hz), 1.0-2.2 (15H, m), 2.27 (2H, broad d, J=7.0 Hz),3.2-4.2 (2H, m), 4.71 (1H, broad s), 5.98 (1H, d, J=14.5 Hz) and 6.73ppm (1H, d of t, J=14.5, 7.5 Hz); ir (CHCl₃) 865, 950, 995, 1025, 1070,1125, 1360, 1445, 2870, and 2950 cm⁻¹.

The synthesis of the PGE₁ analogue was carried out as described inExample 1. The prostaglandin analogue had the following spectralcharacteristics: [α]D-51.7° (c 0.99, CHCl₃); R_(f) (system II) 0.26;mass spectrum m/e 348 (M⁺ -H₂ O) 330 (M⁺ -2H₂ O) 254 (M⁺ -C₇ H₁₃ O); NMR(CDCl₃) δ 0.90 (broad d, 3) 2.6-4.3 (complex, 4) 3.60 (broad t, 2) 5.52(m, 2); ir (CHCl₃) 3600, 3400 (broad) 1740, 970, 950 cm⁻¹.

EXAMPLE 10 16,18-Methano-1,11α,16RS-trihydroxyprost-13E-en-9-one (TR4770)

A solution of 3-ethylcyclobutanone, prepared as described below, wassubstituted for the 2-hexanone of Example 1.

A -10° slurry of 11.4 g of lithium aluminum hydride and 160 ml of etherwas stirred together in a 2 liter 3-necked flask equipped with a refluxcondenser, argon inlet, addition funnel and mechanical stirring. Asolution of 37.6 g of diethyl ethylmalonate, in 40 ml ether was addeddropwise. After addition was complete, the reaction mixture was refluxedfor 1.5 hours. The reaction mixture was cooled in an ice bath and 16 mlof ethyl acetate added, followed by 12 ml of water, 12 ml of 15 percentaqueous sodium hydroxide and 20 ml of water. The reaction mixture wasstirred at 25° for one hour, then filtered and the cake washed withether. The organic layer was isolated, washed with brine, dried overMgSO₄, filtered, and evaporated in vacuo. The resultant oil wasdistilled (aspirator vacuum) to yield 10.5 g of(2-ethylpropane)-1,3-diol as a clear oil (bp 115°). The material had thefollowing spectral characteristics: nmr (CDCl₃) δ 0.8 to 1.9 (6H, m) and3.75 ppm (6H, m); ir (film) 960, 1000, 1035, 1090, 1380, 1460, 2870,2930, 2960, and 3200 to 3600 cm⁻¹.

A solution of 10.5 g of the (2-ethyl)propane-1,3-diol, in 155 ml of drypyridine was stirred at -10° under argon and 48 g of toluenesulfonylchloride was added in small portions. The reaction mixture was stirredfor 4.5 hours at -10°, then poured into 620 ml of 6N HCl (chilled). Themixture was acidified and the aqueous layer extracted with ether. Theextracts were combined and washed with saturated aqueous sodiumbicarbonate, and brine, dried over MgSO₄, filtered and evaporated invacuo to yield an orange oil. NMR spectrum indicated 50 percentreaction. The oil was redissolved in 155 ml pyridine, cooled to -10° andtreated with 31.0 g of toluenesulfonyl chloride. The reaction mixturewas stirred for 1.5 hours at -10°, then stored at 0° for 16 hours. The1,1-di(toluenesulfonyloxymethyl)propane was a white solid. The materialhad the following spectral characteristics: nmr (CDCl₃) δ 0.6 to 2.5(6H, m), 2.42 (6H, s), 3.92 (4H, d, J=5 Hz), 7.32 (4H, d, J=8 Hz) and7.74 ppm (4H, d, J=8 Hz); ir (CHCl₃) 810, 840, 950, 1100, 1175, 1360,2890, 2970 and 3030 cm⁻ 1.

A portion of 5.9 g sodium metal g was granulated in 40 ml xylene bystirring vigorously at 120° under argon in a 1 liter three-neckedround-bottomed flask equipped with a reflux condenser, argon inlet,addition funnel and mechanical stirring. An additional 138 ml of xylenewas added and the heating bath removed. Diethyl malonate (39 ml) wasadded dropwise and the reaction mixture heated to 95° for 15 minutes. Asolution of 48.0 g of 1,1-di(toluenesulfonyloxymethyl)propane in 150 mlxylene was added dropwise. The yellow reaction mixture was refluxed at150°-160° and stirred 18 hours, then cooled and 170 ml water added. Thelayers were separated and the aqueous layer acidified with 10 percentHCl. The aqueous layer was extracted with ether. The organic layers werecombined, washed with brine, dried over MgSO₄, filtered through Celite,evaporated in vacuo and distilled (oil pump vacuum) to afford 11.4 g of1,1-bis-(ethoxycarboxyl)-3-ethylcyclobutane as a clear oil (bp98°-105°). The material had the following spectral characteristics: nmr(CDCl₃) δ 0.76 (3H, t, J=7.0 Hz), 1.24 (6H, t, J=7.0 Hz), 1.9-2.8 (7H,m) and 4.18 ppm (4H, q, J=7.0 Hz); ir (CHCl₃) 860, 1015, 1145, 1265,1370, 1460, 1725, 2870, 2930 and 2960 cm⁻¹.

A solution of 15.7 g of the 1,1-bis(ethoxycarbonyl)-3-ethyl cyclobutane,in 13 ml of ethanol was added to a stirred solution of 15 g of potassiumhydroxide in 155 ml of ethanol. The reaction mixture was refluxed for2.5 hours under argon. The reaction mixture was cooled and ethanolremoved by evaporation in vacuo. The residue was dissolved in water. Theaqueous solution was extracted twice with ether. The ether wasback-extracted twice with water. The combined aqueous layers wereacidified with 6N HCl and extracted with ether. The extracts were washedwith brine, dried, filtered and evaporated in vacuo to yield 12.7 gramsof a yellow solid. An NMR spectrum indicated that the hydrolysis had notgone to completion. The crude product was dissolved in ethanol (75 ml)and 7.5 g of KOH added. The reaction mixture was stirred 18 hours at25°, then processed as above to yield 10.9 g of3-ethylcyclobutane-1,1-dicarboxylic acid, a light yellow solid. Thematerial had the following spectral characteristics: nmr (CDCl₃) δ 0.80(3H, t, J=7.0 Hz) 1.41, (2H, m), 1.6-3.2 (5H, m) and 11.5 ppm (2H, broads); ir (CHCl₃) 940, 1040, 1170, 1290, 1420, 1705 and 2400-3400 cm⁻¹(broad).

A 10.9 g portion of the 3-ethylcyclobutane-1,1-dicarboxylic acid, washeated to 180°-190° for two hours, followed by distillation (oil pumpvacuum) to obtain 6.6 g of 3-ethylcyclobutane carboxylic acid as a clearoil (bp 95°-97°). The material had the following spectralcharacteristics: nmr (CDCl₃) δ 0.75 (3H, t, J=7.0 Hz), 1.4 (2H, m),1.5-2.7 (5H, m), 2.98 (1H, m) and 11.8 ppm (1H, broad s); ir (CHCl₃)940, 1120, 1250, 1420, 1460, 1700 and 2400-3400 cm⁻¹ (broad).

A solution of 6.61 g of 3-ethylcyclobutane-1-carboxylic acid, in 52 mlof distilled ether was stirred under argon at 0°. Methyllithium (85.0 mlof a 1.53M solution in ether) was added dropwise over a 30 minuteperiod. The reaction mixture was stirred for three hours at 25°, thenquenched with 7.3 water-methanol. The layers were separated, and theaqueous layer extracted with ether. The combined organic layers werewashed with brine, dried, filtered and the solvents evaporated in vacuo.The resultant oil was distilled (aspirator vacuum) to afford 5.5 g of1-acetyl-3-ethylcyclobutane, as a clear oil (bp 64°-67°). The materialhad the following spectral characteristics: nmr (CDCl₃) δ 0.80 and 0.82(3H total, pair of t, each J=7.0 Hz), 1.10 and 1.12 (ca. 1.5H total,pair of s, side product 1-[2-hydroxyprop-2-yl]-3-ethylcyclobutane),1.0-2.4 (7H, m), 2.07 and 2.09 (3H total, pair of s) and 2.7-3.5 ppm(1H, m); ir (CHCl₃) 935, 1175, 1370, 1460, 1705, 2870, 2930 and 2970cm⁻¹, also small 3200-3600 broad and 3600 cm⁻¹ for the side productnoted above.

A solution of 5.5 g of the 1-acetyl-3-ethylcyclobutane, and 10.7 g ofm-chloroperbenzoic acid in 107 ml chloroform was allowed to stand forfive days in the dark. The reaction mixture was cooled via external icecooling and filtered. The filtrate was diluted with CHCl₃ and washedwith 10 percent aqueous sodium thiosulfate, 10 percent aqueous sodiumcarbonate and brine, dried over Na₂ SO₄, and filtered. The solution wassubjected to distillation (aspirator vacuum) to afford 3.55 g of1-acetoxy-3-ethylcyclobutane, as a clear oil (bp 65°-67°). The materialhad the following spectral chracteristics: nmr (CDCl₃) δ 0.82 (3H, t,J=7.0 Hz) 1.10 and 1.12, (same side product noted in the 1-acetylcompound spectra), 1.0-2.5 (7H, m), 2.01 (3H, s) and 4.9 (1H, m); ir(CHCl₃) 950, 1040, 1085, 1205, 1250, 1375, 1460, 1720, 2870, 2925 and2960 cm⁻¹ along with trace of 3200-3600 (broad) and 3600 cm⁻¹ for thesame side product noted in the 1-acetyl the compound spectra.

A solution of the 1-acetoxy-3-ethylcyclobutane, in 200 ml of KOH in 3:1methanol-water was stirred at 25° for 24 hours. The mixture was pouredinto 130 ml of brine and 130 ml of ether. The layers were separated andthe aqueous NaHCO₃ and brine, then dried and filtered. The product wasisolated by vacuum distillation (aspirator) to yield 3.55 g of3-ethyl-cyclobutanol (bp 59°-62°). The material had the followingspectral characteristics: ir (CHCl₃) 935, 1050, 1090, 1110, 1220, 1310,1380, 1460, 2860, 2930, 2970, 3200-3600 (broad) and 3600 cm⁻¹.

A solution of 3.55 g of 3-ethylcyclobutanol in 135 ml dry acetone wasstirred under argon at -10°. Standard Jones Reagent (30.5 ml) was addeddropwise. The reaction mixture was stirred for two hours at -10°, then25 ml of isoproponol was added dropwise and the reaction mixture stirredat -10° for 10 minutes. The supernatant liquid was decanted and filteredinto a separatory funnel. The residue was washed three times with etherand each wash was decanted and filtered. Brine (80 ml) was added to thecombined filtrates and the layers separated. The aqueous layer wasextracted with ether. The combined extracts were washed with saturatedaqueous NaHCO₃ and brine, then dried (MgSO₄) and filtered. Distillationby water aspirator vacuum afforded 1.67 ml of 3-ethylcyclobutanone as aclear oil (bp 74°-75°) having the following spectral characteristics: ir(CHCl₃) 1080, 1110, 1310, 1380, 1460, 1780, 2870, 2925, and 2955 cm⁻¹.

The procedure of Example 1 was used to prepare the correspondingiodovinyl alcohol and the corresponding hydroxyl-protected iodovinylalcohol. The acetylenic alcohol, 3-ethyl-1-(prop-2-ynyl)cyclobutanol hadthe following spectral characteristics: nmr (CDCl₃) δ 0.83 (3H, broad t,J=7.0 Hz) and 1.0-2.5 ppm (11H, m); ir (CHCl₃) 850, 1050, 1125, 1245,2240 (weak), 2870, 2925, 2970, 3300, 3200-3600 (broad) and 3600 cm⁻¹.

The acetylenic alcohol was converted into the corresponding iodovinylalcohol and the corresponding protected iodovinyl alcohol by replacingthe 4-methyloct-1-yn-4RS-ol with the above3-ethyl-1-(prop-2-ynyl)cyclobutanol. The resultant product,1-(3-iodoprop-2E-enyl)-3-ethylcyclobutanol, had the following spectralcharacteristics: nmr (CDCl₃) δ 0.80 (3H, t, J=5 Hz), 1.0-2.2 (7H, m),2.2-2.5 (3H, m) 6.17 (1H, d, J=15 Hz), and 6.67 ppm (1H, d of t, J=15, 7Hz); ir (CHCl₃) 945, 1115, 1285, 1460, 1610, 2860, 2930, 2960, 3200 to3600 (broad) and 3600 cm⁻¹.

The 1-(3-iodoprop-2E-enyl)-3-ethyl-1-(tetrahydropyranyloxy)cyclobutanehad the following spectral characteristics: nmr (CDCl₃) δ 0.80 (3H,broad t, J=6 Hz), 1.0-2.4 (15H, m), 3.2-4.2 (2H, m), 4.78 (1H, broad s),6.13 (1H, d, J=14 Hz) and 6.63 (1H, d of t, J=14, 7 Hz); ir (CHCl₃) 860,945, 980, 1020, 1070, 1125, 1280, 1610, 2850, 2950 cm⁻¹.

The synthesis of the PGE₁ analogue was carried out as described inExample 1. The prostaglandin analogue had the following spectralcharacteristics: [α]_(D) -50.6° (c 0.97, CHCl₃); R_(f) (system II) 0.23;mnr (CDCl₃) δ 0.81 (3H, m), 1.0-3.0 (25H, m), 3.60 (5H, broad s), 4.0(1H, m) and 5.57 (2H, m); ir (CHCl₃) 900, 970, 1080, 960, 1740, 2860,2940 and 3100-3600 cm⁻¹ ; ms (70 eV) m/e 334 (p-H₂ O), 316 (p-2H₂ O),278, 236, 235.

The following R₃ and R₄ ring-closed compounds wherein R₃ and R₄ form abicycloalkyl or bicycloalkenyl compound were prepared as describedbelow.

EXAMPLE 1116,18-methano-17,20-methano-1,11α,16RS-trihydroxyprosta-13E,19-dien-9-one(TR 4803)

A solution of bicyclo[3.2.0]hept-2-en-6-one was substituted for the2-hexanone of Example 1. The bicyclo[3.2.0]hept-2-en-6-one was producedas described below [See Tetrahedron Letters 307 (1970)].

The bicyclo[3.2.0]hept-2-en-6-one had the following spectralcharacteristics: (CDCl₃) δ 2.2-4.2 ppm (6H, m) and 5.83 ppm (2H, m); ir(CHCl₃) 1080, 1150, 1345, 1775, 2860 and 2920 cm⁻¹.

The procedure of Example 1 was followed to obtain the correspondingacetylenic alcohol, the corresponding iodovinyl alcohol and thecorresponding protected iodovinyl alcohol by replacing the4-methyloct-1-yn-4RS-ol with the acetylenic alcohol,6-(prop-2-ynyl)bicyclo[3.2.0]hept-2-en-6RS-ol.

The acetylenic alcohol had the following spectral characteristics: nmr(CDCl₃) δ 1.5-3.2 (10H, m) and 5.83 (2H, m); ir (CHCl₃) 690, 930, 1170,1260, 1350, 1415, 2120 (weak), 2850, 2930, 3300, 3200-3600 (broad) and3570 cm⁻¹.

The 6-(3-iodoprop-2E-enyl)bicyclo[3.2.0]hept-2-en-6RS-ol had thefollowing spectral characteristics: nmr (CHCl₃) δ 1.5-3.2 (9H, m), 5.82(2H, m), 6.10 (1H, d, J=14 Hz) and 6.59 ppm (1H, d of t, J=14, 7 Hz).

The6-(3-iodoprop-2E-enyl)-6RS-(tetrahydropyranyloxy)-bicyclo[3.2.0]hept-2-enehad the following spectral characteristics: nmr (CDCl₃) δ 1.2-3.0 (14H,m), 3.2-4.2 (2H, m), 4.60 (1H, broad s), 5.77 (2H, broad s), 6.08 (1H,d, J=14 Hz) and 6.60 ppm (1H, d of t, J14, 7 Hz); ir (CHCl₃) 870, 910,990, 1030, 1075, 1130, 1610, 2860 and 2950 cm⁻¹.

The synthesis of the PGE₁ analogue was carried out as described inExample 1. The prostaglandin analogue had the following spectralcharacteristics:

[α]_(D) -43.9° (c 1.0, CHCl₃); R_(f) (system II) 0.27; nmr (CDCl₃) δ1.0-3.2 (28H, m), 3.63 (2H, t, J=6.0 Hz), 4.0 (1H, m) and 5.5-6.1 ppm(2H, m); ir (CHCl₃) 970, 1070, 1160, 1230, 1350, 1430, 1740, 2860, 2930and 3200-3600 cm⁻¹ ; ms (70 eV) m/e 362 (p), 344 (p-H₂ O), 326, 296,278, 261, 233.

EXAMPLE 1216,18-Methano-17,20-ethano-1,11α,16RS-trihydroxyprost-13E-en-9-one and16,18-Methano-17,20-ethano-1,16RS-dihydroxyprosta-10,13E-dien-9-one (TR4804 and TR 4806)

A solution of bicyclo[4.2.0]octan-7-one was substituted for the2-hexanone of Example 1. The bicyclo[4.2.0]octan-7-one was prepared asdescribed in Tetrahedron Letters 4753 (1971).

The bicyclo[4.2.0]oct-2-en-7-one compound was converted intobicyclo[4.2.0]octan-7-one as follows.

A solution of 4.2 g of bicyclo[4.2.0]oct-2-en-7-one in isopropanol,total solution of 100 ml, was hydrogenated over 0.5 g of platinum oxideat 50 PSI of hydrogen in a Parr shaker for 18 hours. The catalyst wasremoved by filtration and the filtrate was evaporated to yield 3.2 g ofthe compound, having the following spectral characteristics: nmr 0.8 to3.5 ppm (m); ir 1040, 1090, 1450, 1765, 2860 and 2930 cm⁻¹.

The procedure of Example 1 was followed to obtain the correspondingacetylenic alcohol, the corresponding iodovinyl alcohol and thecorresponding protected iodovinyl alcohol by replacing4-methyloct-1-yn-4RS-ol with the acetylenic alcohol,7-(prop-2-ynyl)bicyclo[4.2.0]octan-7RS-ol. The acetylenic alcohol hadthe following spectral characteristics: nmr (CDCl₃) δ 1.0-2.2 (13H, m),2.28 (1H, s) and 2.47 ppm (2H, d, J=2.5 Hz); ir (CHCl₃) 900, 1070, 1140,1260, 1460, 2120 (weak), 2860, 2930, 3300, 3200 to 3600 (broad) and 3570cm⁻¹.

The 7-(3-iodoprop-2E-enyl)bicyclo[4.2.0]octan-7RS-ol had the followingspectral characteristics: nmr (CDCl₃) δ 1.0-2.2 (13H, m), 2.37 (2H, d,J=6 Hz), 6.10 (1H, d, J=41 Hz) and 6.72 ppm (1H, d of t, J=14, 7 Hz); ir(CHCl₃) 905, 950, 1075, 1100, 1130, 1260, 1455, 1610, 2850, 2930,3200-3600 (broad) and 3600 cm⁻¹.

The7-(3-iodoprop-2E-enyl)-7RS-(tetrahydropyranyloxy)bicyclo[4.2.0]octanehad the following spectral characteristics: nmr (CDCl₃) δ 0.8-2.6 (20H,m), 3.2-4.2 (2H, m), 4.57 (1H, broad s), 6.02 (1H, d, J=14 Hz) and6.3-6.9 (1H, m); ir (CHCl₃) 870, 945, 975, 1020, 1070, 1120, 1270, 1450,2850 and 2940 cm⁻¹.

The synthesis of the PGE₁ analogue was carried out as described inExample 1. A small amount of the PGA₁ prostaglandin analogue wasproduced as a side-product. The prostaglandin analogues had thefollowing spectral characteristics:

TR 4804-[α]_(D) -44.6° (c 1.0, CHCl₃); R_(f) (system II) 0.34;nmr(CDCl₃) δ 1.0-3.2 (32H, m), 3.58 (2H, t, J=6.0 Hz), 3.98 (1H, m) and5.56 ppm (2H, m); ir (CHCl₃) 900, 970, 1070, 1150, 1240, 1345, 1460,1740, 2860, 2970 and 3200-3600 CM⁻¹ ; ms (70 eV) m/e 378 (p), 360 (p-H₂O), 296, 278, 236.

TR 4806-[α]_(D) +64.4° (c 1.0, CHCl₃); R_(f) (system II) 0.51; nmr(CDCl₃) 1.0-2.7 (29H, m), 3.24 (1H, m), 3.62 (2H, t, J=6.0 Hz), 4.03(1H, m), 5.60 (2H, m) 6.14 (1H, m) and 7.50 ppm (1H, m); ir (CHCl₃) 930,970, 1050, 1140, 1215, 1340, 1455, 1595, 1700, 2860, 2930, 3200-3600 and3600 cm⁻¹ ; ms (70 eV) m/e (360 (p), 278, 236, 217.

EXAMPLE 1316,18-Methano-17,20-methano-1,11α,16RS-trihydrosyprost-13E-en-9-one and16,18-Methano-17,20-methano-1,11α,16RS-trihydroxyprosta-10,13E-dien-9-one(TR 4799 and TR 4805)

A solution of bicyclo[3.2.0]hept-2-en-6-one, prepared as described inExample 11, was substituted for the bicyclo[4.2.0]oct-2-en-7-one ofExample 12 to prepare bicyclo[3.2.0]heptan-6-one. Thebicyclo[3.2.0]heptan-6-one had the following spectral characteristics:nmr (CDCl₃) δ 1.0-3.8 ppm(m); ir (CHCl₃) 905, 1080, 1220, 1385, 1450,1770, 2870 and 2950 cm⁻¹.

The procedure of Example 1 was followed to obtain the correspondingacetylenic alcohol, corresponding iodovinyl alcohol and correspondingprotected iodovinyl alcohol by replacing the 4-methyloct-1-yn-4RS-olwith the acetylenic alcohol, 6-(prop-2-ynyl)bicyclo[3.2.0]heptan-6RS-ol.The acetylenic alcohol had the following spectral characteristics: nmr(CDCl₃) δ 1.0-2.2 (11H, m), 2.15 (1H, s) and 2.45 ppm (2H, d, J=2.5 Hz);ir (CHCl₃) 910, 1775, 1140, 1265, 1460, 2115 (weak), 2870, 2930 3300,3200 to 3600 (broad) and 3590 cm⁻¹.

The 6-(3-iodoprop-2E-enyl)bicyclo[3.2.0]heptan-6RS-ol had the followingspectral characteristics: nmr (CDCl₃) δ 1.0-2.0 (10H, m), 2.30 (2H, d,J=6.5 Hz), 2.4 (1H, broad s), 6.13 (1H, d, J14 Hz) and 6.63 ppm (1H, dof t, J14, 7 Hz); ir (CHCl₃) 950, 1070, 1200, 1260, 1605, 2850, 2940,3200-3600 (broad) and 3600 cm⁻¹.

The6-(3-iodoprop-2E-enyl)-6RS-(tetrahydropyranyloxy)bicyclo[3.2.0]heptanehad the following spectral characteristics: nmr (CDCl₃) δ 1.0-2.7 (18H,m), 3.2-4.2 (2H, m), 4.58 (1H, broad s), 6.02 (1H, d, J=14 Hz) and6.2-6.9 ppm (1H, m); ir (CHCl₃) 865, 970, 1010, 1070, 1120, 1180, 1270,1430, 1610, 2850, and 2940 cm⁻¹.

The synthesis of the PGE₁ analogue was carried out as described inExample 1. A small amount of the PGA₁ prostaglandin analogue wasproduced as a side-product. The prostaglandin analogues had thefollowing spectral characteristics:

TR 4799-[α]_(D) -52.8° (c 1.0, CHCl₃): R_(f) (system II) 0.26; nmr(CDCl₃) 1.0-3.0 (31H, m), 3.65 (2H, t, J=6.0 Hz), 4.01 (1H, m) and 5.60ppm (2H, m); ir (CHCl₃) 900, 970, 1070, 1260, 1740, 2860, 2930, and3200-3600 cm⁻¹ ; ms (70 eV) m/e 364 (p), 346 (p-H₂ O), 328, 278, 260,236, 217.

TR 4805-[α]_(D) +77.8° (c 1.0, CHCl₃); R_(f) (system II) 0.55; nmr(CDCl₃) δ 1.1-2.8 (27H, m), 3.29 (1H, m), 3.66 (2H, t, J=6.0 Hz), 4.06(1H, m), 5.61 (2H, m), 6.17 (1H, m) and 7.49 ppm (1H, m); ir (CHCl₃)910, 970, 1060, 1245, 1350, 1705, 2860, 2930, and 3200-3600 cm⁻¹ ; ms(70 eV) m/e 346 (p), 278, 260, 236, 217.

EXAMPLE 1416,20-Methano-17,20-methano-1,11α,16RS-trihydroxyprost-13E-en-9-one (TR4903)

The procedures of Example 1 were followed to obtain the correspondingacetylenic alcohol, corresponding iodovinyl alcohol and correspondingprotected iodovinyl alcohol by replacing the 2-hexanone withcommercially available bicyclo[2.2.1]heptan-2-one.

The acetylenic alcohol had the following spectral characteristics; nmr(CDCl₃) δ 1.0-2.8 (10H, m), 2.03 (1H, t, J=2.2 Hz) and 2.42 ppm (2H, d,J=2.2 Hz); ir (CHCl₃) 995, 1035, 1160, 1270, 1735, 2950, 3300 and3200-3600 cm⁻¹ (broad).

The 2-(2-iodoprop-2E-enyl)bicyclo[2.2.1]heptan 2RS-ol had the followingspectral characteristics: nmr (CDCl₃) δ 0.8-2.6 (13H, m), 6.07 (1H, d,J=14.5 Hz) and 6.60 ppm (1H, d of t, J=14.5, 7 Hz); ir (CHCl₃) 950,1030, 1180, 1205, 1305, 2950 and 3300-3700 cm⁻¹ (broad).

The 2-(3-iodoprop-2Eenyl)-2RS-(tetrahydropyranyloxy)bicyclo[2.2.1]heptane had the followingspectral characteristics: nmr (CDCl₃) δ 0.8-2.6 (16H, m), 3.2-42 (2H,m), 4.65 (1H, broad s), 6.0 (1H, d, J=14.5 Hz) and 6.1-6.9 ppm (1H, m);ir (CHCl₃) 860, 970, 1020, 1070, 1120 and 2940 cm⁻¹.

The synthesis of the PGE₁ analogue was carried out as described inExample 1. The prostaglandin analogue had the following spectralcharacteristics:

TR 4903-[α]_(D) -43.4° (c 1.07, CHCl₃); R_(f) (system II) 0.25; nmr(CDCl₃) δ 0.8-3.0 (31H, m), 3.65 (2H, t, J=5.8 Hz), 4.0 (1H, m) and 5.6ppm (2H, m); ir (CHCl₃) 900, 970, 1070, 1155, 1260, 1740, 2930 and3200-3600; ms (70 eV) m/e 346 (p-H₂ O).

EXAMPLE 15 17,20-Methano-17-methyl-1,11α,16R andS-trihydroxyprost-13E-en-9-one (TR 4982 and TR 4983)

The procedures of Example 3 were followed to obtain1-methyl-1-cyclopentane carboxaldehyde by replacing 2-methylpropionicacid with commercially available cyclopentanecarboxylic acid and furtherreplacing n-propyliodide with commercially available methyliodide. Theprocedures of Example 1 were then followed to obtain the correspondingacetylenic alcohol, corresponding iodovinyl alcohol and correspondingprotected iodovinyl alcohol by replacing the 2-hexanone with1-methyl-1-cyclopentanecarboxaldehyde.

The 1-methyl-1-cyclopentanecarboxylic acid had the following spectralcharacteristics: nmr (CDCl₃) δ 1.27 (3H, s), 1.0-2.5 (8H, m) and 11.2ppm (1H, s); ir (CHCl₃) 940, 1200, 1280, 1410, 1455, 1700 and 2400-3400cm⁻¹ (broad).

The intermediate 1-methyl-1-cyclopentanemethanol had the followingspectral characteristics: nmr (CDCl₃) δ 1.0 (3H, s), 1.0-2.0 (8H, m),2.42 (1H, broad s) and 3.38 ppm (2H, broad s).

The 1-methyl-1-cyclopentanecarboxaldehyde had the following spectralcharacteristics: nmr (CDCl₃) δ 1.12 (3H, s), 1.0-2.2 (8H, m) and 9.50ppm (1H, s).

The acetylenic alcohol had the following spectral characteristics: nmr(CDCl₃) δ 0.93 (3H, s), 1.0-2.5 (11H, m), 3.0 (1H, broad s) and 3.6 ppm(1H, m); ir (CHCl₃) 840, 1060, 1200, 1380, 1450, 1660, 2950, 3300 and3300-3650 cm⁻¹.

The 4-(1-methylcyclopentyl)-1-iodobut-1E-en-4RS-ol had the followingspectral characteristics: nmr (CDCl₃) δ 0.93 (3H, s), 1.0-2.4 (11H, m),3.43 (1H, m), 6.12 (1H, d, J=14.5 Hz) and 6.70 ppm (1H, d of t, J=14.5,7.2 Hz); ir (CHCl₃) 945, 1060, 1270, 1380, 1450, 2960 and 3300-3600cm⁻¹.

The 4-(1-methylcyclopentyl)-1-iodo-4RS-(2-ethoxyethoxy)but-1R-ene hadthe following spectral characteristics: nmr (CDCl₃) δ 0.90 (3H, s),1.0-2.0 (14H, m), 2.30 (2H, t, J=6.2 Hz); 3.2-3.9 (3H, m), 4.75 (1H, m),6.10 (1H, d, J=14.5 Hz) and 6.3-7.1 ppm (1H, m); ir (CHCl₃) 950, 1050,1090, 1120, 1380, 1450 and 2950 cm⁻¹.

The synthesis of the PGE₁ analogue was carried out as described inExample 1. The prostaglandin analogue isomers were separated by columnchromatography and had the following spectral characteristics:

TR 4983-More Polar Isomer-[α]_(D) -57.7° (c 1.0, CHCl₃); R_(f) (systemII) 0.31; nmr (CDCl₃) δ 0.93 (3H, s), 1.0-3.0 (29H, m), 3.2-4.3 (4H, m)and 5.51 ppm (2H, m); ir (CHCl₃) 970, 1070, 1160, 1230, 1740, 2930 and3200-3650 cm⁻¹ ; ms (70 eV) m/e 348 (p-H₂ O).

TR 4982-Less Polar Isomer-[α]_(D) -42.5° (c 1.0, CHCl₃); R_(f) (systemII) 0.33; nmr, ir and ms essentially the same as TR 4983 above.

EXAMPLE 16 17,17-Propano-1,11α,16R-trihydroxyprost-13E-en-9-one and17,17-Propano-1,11α,16S-trihydroxyprost-13E-en-9-one (TR 4984 and TR4985)

The procedures of Example 3 were followed to obtain1-propyl-1-cyclobutanecarboxaldehyde by replacing 2-methylpropionic acidwith commercially available cyclobutanecarboxylic acid. The proceduresof Example 1 were then followed to obtain the corresponding acetylenicalcohol, corresponding iodovinyl alcohol and corresponding protectediodovinyl alcohol by replacing the 2-hexanone with1-propyl-1-cyclobutanecarboxaldehyde.

The 1-propyl-1-cyclobutanecarboxylic acid had the following spectralcharacteristics: nmr (CDCl₃) δ 0.7-2.8 (13H, complex m) and 11.2 ppm(1H, s); ir (CHCl₃) 930, 1160, 1230, 1255, 1300, 1330, 1410, 1695 and2400-3500 cm⁻¹.

The intermediate 1-propyl-1-cyclobutane-methanol had the followingspectral characteristics: nmr (CDCl₃) δ 0.7-2.2 (14H, m) and 3.52 ppm(2H, s); ir (CHCl₃) 1005, 1230, 1380, 1460, 2930 and 3200-3600 cm⁻¹.

The 1-propyl-1-cyclobutanecarboxaldehyde had the following spectralcharacteristics: nmr (CDCl₃) δ 0.8-2.6 (13H, m) and 9.60 (1H, s); ir(CHCl₃) 1150, 1190, 1460, 1695 and 2970 cm⁻¹.

The acetylenic alcohol had the following spectral characteristics: nmr(CDCl₃) δ 0.8-2.7 (16H, m) and 3.77 ppm (1H, m); ir (CHCl₃) 1060, 1220,1460, 2450, 3300 and 3300-3650 cm⁻¹.

The 4-(1-propylcyclobutyl)-1-iodubut-1E-en-4RS-ol had the followingspectral characteristics: nmr (CDCl₃) δ 0.8-2.5 (16H, m), 3.62 (1H, m),6.13, (1H, d, J14.5 Hz) and 6.67 ppm (1H, d of t, J14.5, 7.3 Hz); ir(CHCl₃) 940, 1050, 1230, 1270, 1460, 2950 and 3300-3650 cm⁻¹.

The 4-(1-propylcyclobutyl)-1-iodo-4RS-(2-ethoxyethoxy)but-1E-ene had thefollowing spectral characteristics: nmr (CDCl₃) δ 0.8-2.3 (21H, m), 3.6(3H, m), 4.7 (1H, m), 6.05 (1H, d, J=14.5 Hz) and 6.6 ppm (1H, d of t,J=14.5, 7.3 Hz); ir (CHCl₃) 950, 1020, 1050, 1090, 115, 1380 and 2940cm⁻¹.

The synthesis of the PGE₁ analogue was carried out as described inExample 1. The prostaglandin analogue isomers were separated by columnchromatography and had the following spectral characteristics:

TR 4985-Polar Isomer-[α]_(D) -56.3° (c 1.04, CHCl₃); R_(f) (system II)0.34; nmr (CDCl₃) δ 0.8-2.7 (34H, m), 3.4-4.3 (4H, m) and 5.57 ppm (2H,m); ir (CHCl₃) 960, 1060, 1150, 1210, 1460, 1740, 2930 and 3200-3600cm⁻¹ ; ms (70 eV) m/e 362 (p-H₂ O).

TR 4984-Less Polar Isomer-[α]_(D) -39.5° (c 0.98, CHCl₃); R_(f) (systemII) 0.35; nmr, ir and ms essentially the same as TR 4985 above.

As referred to earlier, the Searle and Lederle prior art discloses16-hydroxy compounds which are acids and esters. The methyl esteranalogues of the carbinols of Examples 1 (TR 4698); Example 2 (TR 4706);Example 3 (TR 4752) and Example 4 (TR 4749) were prepared in order thatbiological activities of the methyl esters and the carbinols of thepresent invention could be compared.

COMPARATIVE PROCEDURE A Methyl11α,16RS-dihydroxy-16-methyl-9-oxoprost-13E-oate (TR 4704)

The methyl ester was prepared as described in Example 1 by replacing4R-(tetrahydropyran-2-yloxy)-2-[7-(tetrahydropyran-2-yloxy)heptyl]2-cyclopenten-1-onewith4R-(tetrahydropyran-2-yloxy)-2-(6-carbomethoxyhexyl)cyclopent-2-en-1-onewas prepared as described by Sih et al., J. Amer. Chem. Soc., 97, 865.

The PGE₁ ester analogue had the following spectral characteristics:[α]_(D) -71.8° (c 1.0, CHCl₃); R_(f) (system II) 0.41; nmr (CDCl₃) δ0.93 (3H, m), 1.0-2.8 (24H, m), 1.18 (3H, s), 3.47 (2H, broad s), 3.72(3H, s), 4.07 (1H, m) and 5.66 ppm (2H, m); ir (CHCl₃) 900, 970, 1075,1160, 1230, 1380, 1440, 1730, 2860, 2930, and 3200-3600 cm⁻¹ ; ms (70eV) m/e 367 (p-CH₃), 364 (p-H₂ O), 351, 346, 333, 325, 315, 306.

COMPARATIVE PROCEDURE B Methyl11α,16RS-dihydroxy-9-oxoprost-13E-en-1-oate (TR 4705)

The methyl ester was prepared as described in Example 2 by replacing4R-(tetrahydropyran-2-yloxy)-2-[7-(tetrahydropyran-2-yloxy)heptyl]2-cyclopenten-1-onewith the cyclopentanone ester prepared as described by Sih et al.,Comparative Procedure A.

The PGE₁ methyl ester analogue had the following spectralcharacteristics: [α]_(D) -62.2° (c 1.0, CHCl₃); R_(f) (system II) 0.43;nmr (CDCl₃) δ 0.95 (3H, m), 1.0-2.8 (26H, m), 3.73 (3H, s), 3.89 (2H,broad s), 4.15 (2H, m), and 5.67 ppm (2H, m); ir (CHCl₃) 900, 970, 1080,1170, 1250, 1340, 1440, 1730, 2860, 2970 and 3200-3600 cm⁻¹ ; ms (70 eV)m/e 350 (p-H₂ O), 319 (p-H₂ O-CH₃ O), 301, 282, 279, 264, 232, 222, 210,204.

COMPARATIVE PROCEDURE C Methyl 11α,16R andS-dihydroxy-17,17-dimethyl-9-oxoprost-13E-en-1-oate (TR 4836)

The methyl ester was prepared as described in Example 3 by replacing4R-(tetrahydropyran-2-yloxy)-2-[7-(tetrahydropyran-2-yloxy)heptyl]2-cyclopenten-1-onewith the cyclopentanone ester prepared as described by Sih et al.,Comparative Procedure A.

The PGE₁ methyl ester analogue had the following spectralcharacteristics:

TR 4836-More Polar Isomer-[α]_(D) -59.1° (c 1.12, CHCl₃); R_(f) (systemII) 0.49; nmr (CDCl₃) δ 0.90 (9H, broad s), 1.0-3.1 (22H, m), 3.1-4.2(4H, m), 3.67 (3H, s) and 5.52 ppm (2H, m); ir (CHCl₃) 870, 970, 1075,1170, 1220, 1370, 1445, 1730, 2860, 2930 and 3200-3600 cm⁻¹ ; ms (70 eV)m/e 378 (p-H₂ O), 365, 360, 347, 329, 311, 293, 282, 264, 262, 232, 222,210, 204, 200.

TR 4835-Less Polar Isomer-[α]_(D) -54.9° (c 0.69, CHCl₃); R_(f) (systemII) 0.54; nmr, ir and ms essentially the same as isomeric TR 4836, ie,more polar isomer above.

COMPARATIVE PROCEDURE D Methyl11α,16RS-dihydroxy-17-methyl-9-oxoprost-13E-oate (TR 4814)

The methyl ester was prepared as described in Example 4 by replacing4R-(tetrahydropyran-2-yloxy)-2-[7-(tetrahydropyran-2-yloxy)heptyl]2-cyclopenten-1-onewith the cyclopentanone ester prepared as described in Sih et al.,Comparative Procedure A.

The PGE₁ methyl ester analogue had the following spectralcharacteristics: [α]_(D) -65.0° (c 0.98, CHCl₃); R_(f) (system II) 0.49;nmr (CDCl₃) δ 0.90 (6H, m), 1.0-3.1 (23H, m), 3.57 (2H, broad s), 3.66(3H, s), 4.10 (2H, m) and 5.54 ppm (2H, m); ir (CHCl₃) 970, 1070. 1160,1230, 1370, 1440, 1735, 2860, 2940 and 3200-3600 cm⁻¹ ; ms (70 eV) m/e382 (p), 364, 351, 346, 333, 315, 311, 282, 264, 232, 222, 210, 204,200.

Compounds of this invention were screened to detect the followingbiological activities:

BIOLOGICAL ACTIVITIES

(A) effects on the rat stomach, rat colon, chick rectum, and rabbitaorta in vitro (cascade assay);

(B) effect on the rat uterus in vitro;

(C) effect on the guinea pig trachea in vitro;

(D) antagonism of the effects of PGE₁ and PGF₂α on the guinea pig ileumin vitro;

(E) effect on human platelet aggregation in vitro; and

(F) effect on gastric secretion in the rat.

In addition, certain of the compounds were tested for the followingbiological activities:

(G) effect on blood pressure and heart rate in the anesthetized cat;

(H) effect on femoral blood flow in the anesthetized dog; and

(I) effect on systolic blood pressure in the hypertensive rat.

A. Evaluation of Cascade Assay Effects

The smooth muscle stimulant effects of the test compounds weredetermined simultaneously in four different tissues that are known to bereactive to naturally occurring prostaglandins. Segments of rat stomachfundus, rat colon, chick rectum and rabbit aortic strip were obtained asdescribed by: Vane, J. R., Brit. J. Pharmacol., 12: 344 (1957); Regoli,D. and Vane, J. R., Brit. J. Pharmacol., 23: 351 (1964); Mann, M. andWest, G. B., Brit. J. Pharmacol., 5: 173 (1950); and Furchgott, R. F.and Bhadrakom, R., J. Pharmacol. Exper. Ther., 108: 129 (1953). One endof each preparation was tied to the bottom of a 10 ml tissue chamber andthe other to a force displacement transducer (Grass FT-03) forcontinuous tension recording. The stomach, colon, and rectum segmentswere stretched to an initial tension of 1 g, while the aortic strip wassubjected to 4 g. All preparations were left undisturbed for 1 hourprior to ptesting. The chambers were equipped with an external jacketthrough which water, maintained at 40° C., was circulated. Preparationswere arranged one beneath the other in descending order (aorta, stomach,colon and rectum). Provision was made for bathing the four tissuessuccessively so that they were superfused with the same fluid (Gaddum,J. H., Brit. J. Pharmacol., 6: 321 [1953] ). The bathing fluid consistedof: Krebs bicarbonate solution aerated with a mixture of 95% O₂ and 5%CO₂ and warmed at 37° C.; atropine sulphate (0.1 mcg/ml),phenoxybenzamine hydrochloride (0.1 mcg/ml), propranolol hydrochloride(3.0 mcb/ml), methysergide maleate (0.2 mcb/ml) and brompheniraminemaleate (0.1 mcg/ml) were added to eliminate the possibility of smoothmuscle responses being due to stimulation of cholinergic, adrenerigic,serotonin or histamine receptors. The fluid was circulated by means of aroller pump and was allowed to drip over the preparations at a rate of10 ml/minute.

Test compounds were diluted from stock solutions so as to administerquantities ranging from 0.0001 to 100,000 ng in a volume of 0.5 ml. Thecompounds were applied by dripping on the uppermost tissue, at intervalsof 10 to 20 minutes. Maximal increases in tension after each dose weremeasured and the results were used to plot dose-response curves. ED₅₀data (doses necessary to produce a response 50% of maximum) were thencalculated graphically for each tissues. Maximum responses utilized werethose elicited by PGE₁ in gastric and rectal tissue, by PGF₂α in colonictissue, and by PGA₂ in aortic tissue.

Activity in each tissue was scored according to the following scale:

    ______________________________________                                        ED.sub.50, ng Activity Value                                                  ______________________________________                                        >10000        0                                                               1001-10000    1                                                               101-1000      2                                                               10-100        3                                                                 <10         4                                                               ______________________________________                                    

B. Evaluation of the Effects on the Rat Uterus in Vitro

The uterine stimulant effect of test compounds was determined insegments of uterus obtained from rats (140-160 g) pretreatedsubcutaneously with 1 mg/kg of diethylstilbesterol 18 hours before theexperiment. The tissues were placed in 10 ml chambers filled withde-Jalon solution at 29° C., were aerated and bubbled with 95% O₂ and 5%CO₂, and were prepared for isometric recording with force displacementtransducers. Preparations were stretched to an initial tension of 1 gand were left undisturbed for 30 minutes. Carbachol (1 mcg/ml) was thenadded to the bath and a response was recorded. After a ten minuteinterval the carbachol procedure was repeated. Responses to increasingconcentrations of a test compound (0.001 to 10 mcg/ml with one logintervals) were then recorded every 10 minutes. Preparations were washedfour times after each response. All doses of compounds were administeredin a 0.1 ml volume. Because it has been observed that the magnitude ofthe second response to carbachol (approximately 10% greater than thefirst) is close to the maximal response of the tissue, such value wastaken as a measure of the sensitivity of a particular segment. Responsesto each concentration of the test compound were expressed in terms ofpercentage of the second response to carbachol and the ED₅₀ (doseproducing a response 50% that of carbachol) was calculated graphically.Activity was scored according to the following scale:

    ______________________________________                                        ED.sub.50 (mcg/ml)                                                                           Activity Value                                                 ______________________________________                                        >10            0                                                              1.001-10       1                                                              0.101-1.0      2                                                               0.01-0.1      3                                                              <0.01          4                                                              ______________________________________                                    

C. Evaluation of the Effects on the Guinea Pig Trachea in Vitro

A male guinea pig weighing 200-500 g was killed by a blow on the head. A20 mm length of the trachea was dissected from the animal, transferredto a petri dish containing Krebs' solution (aerated with 95% O₂ and 5%CO₂ at 37° C.), and cut longitudinally opposite the tracheal muscle. Thetissue was then cut transversely three quarters of the distance across,a second cut in the opposite direction (again three quarters of thedistance across the tissue) was made and the procedure was continued forthe whole tissue. The ends of the trachea were pulled to form a zig-zigshaped strip. The tracheal strip used in the experiment wasapproximately 30 mm when extended under 0.25-0.5 g load in the tissuebath. Cotton thread was tied to one end of the tissue, and linen threadto the other. It was attached via the linen thread to a glass hook in a5 ml isolated tissue bath containing Krebs' solution (37° C., aeratedwith a mixture of 95% O₂ and 5% CO₂). The opposite end was attached viacotton to an isotonic Harvard transducer (Model 386 Heart/Smooth MuscleTransducer, Harvard Apparatus). The load on the transducer lever wassmall, usually 0.3 g, with a range of 0.25-0.5 g, and the magnificationhigh, 80 fold using an appropriate twin-channel pen recorder. A minimumof thirty minutes was allowed before applying a test compound to thetissue. Test compounds were then applied (in volumes of 0.5 ml) atthirty minute intervals, being in contact with the tissue for fiveminutes followed by an overflow washout time of twenty seconds.

Prostaglandin E₁, at a bath concentration of 0.1 mcg/ml, was then testedrepeatedly on two such strips, obtained from two different animals,until two responses (the values of which are recorded) differing by nomore than 25% occur. A test compound was then added to the same twostrips at bath concentrations of 0.01, 0.1, 1.0, and 10.0 mcg/ml and theeffects of the compound were recorded. After the test compound had beenevaluated at the highest concentration, PGE₁ was retested at 0.1 mcg/ml(and the value of the response recorded) to insure that the viability ofthe strips was retained during the experiment. The mean of the effectsof the test compound on the two strips was then calculated for eachconcentration, and, based on the resulting values, an activity value wasassigned as follows:

    ______________________________________                                        Response              Activity Value                                          ______________________________________                                        More relaxation at 0.01 mcg/ml                                                                      R4                                                      than that elicited by PGE.sub.1                                               More relaxation at 0.1 mcg/ml                                                                       R3                                                      than that elicited by PGE.sub.1                                               More relaxation at 1.0 mcg/ml                                                                       R2                                                      than that elicited by PGE.sub.1                                               More relaxation at 10.0 mcg/ml                                                                      R1                                                      than that elicited by PGE.sub.1                                               No effect at any concentration                                                                      0                                                       greater than that elicited                                                    by PGE.sub.1                                                                  More contraction at 10.0 mcg/ml                                                                     C1                                                      than the degree of relaxation                                                 elicited by PGE.sub.1                                                         More contraction at 1,0 mcg/ml than                                                                 C2                                                      the degree of relaxation                                                      elicited by PGE.sub.1                                                         More contraction at 0.1 mcg/ml than                                                                 C3                                                      the degree of relaxation                                                      elicited by PGE.sub.1                                                         More contraction at 0.01 mcg/ml than                                                                C4                                                      the degree of relaxation                                                      elicited by PGE.sub.1                                                         ______________________________________                                    

D. Evaluation of Antagonistic Effects on the Guinea Pig Ileum in Vitro

The degree and specificity of antagonism of test compounds to the smoothmuscle stimulant effects of prostaglandins were assessed in segments ofterminal guinea pig ileum. Preparations were placed in tissue chambersfilled with Ringer-Tyrode solution at 37° C., bubbled with a mixture of95% O₂ and 5% CO₂, and arranged for isometric recording with forcedisplacement transducers. The segments were stretched to an initialtension of 1 g, and responses to a test concentration of acetylcholine(0.1 mcg/ml) were obtained every 5 minutes until two similar responseswere observed (usually after four administrations). Responses toacetycholine (0.1 mcg/ml), PGE₁ (0.1 mcg/ml), BaCl₂ (100 mcg/ml) andPGF₂α (1 mcg/ml) were obtained (and recorded) in that order at 5 minuteintervals before and after 100 seconds of incubation with 0.1 and 1.0mcg/ml of the test compound. Any direct contractile effect of the testcompound was recorded and evaluated in terms of mean values in grams oftension developed at each concentration. Responses to the differentagonists observed after incubation with the test compound were expressedas percent of control responses. All drugs were administered in a volumeof 0.1 ml.

Antagonism to prostaglandins was scored independently for PGE₁ and PGF₂αaccording to the following criteria:

    ______________________________________                                        Response              Activity Value                                          ______________________________________                                        Less than 50% blockade of PG response                                                               0                                                       More than 50% blockade of PG responses                                                              1                                                       and more than 10% antagonism of Ach                                           and/or BaCl.sub.2, or production of direct                                    contraction                                                                   More than 50% blockage of PG responses                                                              2                                                       at 1 mcg/ml with less than 11% antago-                                        nism of Ach and BaCl.sub.2 without produc-                                    tion of direct contraction                                                    ______________________________________                                    

E. Evaluation of Inhibition of Human Platelet Aggregation

The ability of test compounds to inhibit platelet aggregation wasdetermined by a modification of the turbidometric technique of Born, G.V. R. (Nature, 194: 927 [1962]). Blood was collected from humanvolunteers, who had not ingested aspirin or aspirin-containing productswithin the preceding two weeks, in heparinized containers and wasallowed to settle for one (1) hour. The platelet rich plasma (prp)supernates were collected and pooled. Siliconized glassware was usedthroughout.

In a representative assay, 1.9 ml of PRP and 0.2 ml of test compound atthe appropriate concentration (0.001 to 100 mc/gm), or 0.2 ml ofdistilled water (control procedure) were placed in sample cuvettes. Thecuvettes were placed in a 37° C. incubation block for 15 minutes, andthen in a spectrophotometer linked to a strip chart recorder. After30-60 seconds, 0.2 ml of a solution, prepared by diluting a calf-skincollagen solution 1:9 with Tyrodes' Solution, was added to each cuvette.Platelet aggregation was evidenced by a decrease in optical density.

Calculation of the degree of inhibition of platelet aggregationexhibited by each concentration of test compound was accomplishedaccording to the method of Caprino et al., (Arzneim-Forsch., 23: 1277[1973]). An ED₅₀ value was then determined graphically. Activity of thecompounds was scored as follows:

    ______________________________________                                        ED.sub.50 (mcg/kg)                                                                            Activity Value                                                ______________________________________                                        >1.0            0                                                             >0.1 and <1.0   1                                                             >0.01 and <0.1  2                                                             >0.001 and <0.01                                                                              3                                                             <0.001          4                                                             ______________________________________                                    

F. Evaluation of the Effects on Gastric Secretion in the Rat

A procedure based on that described by Lipman, W. (J. Pharm. Pharmacol.,21: 335 [1968]) was used to assess the influence of test compounds ongastric secretion. Rats of one sex weighing 150 to 200 g were randomlydivided into groups of six animals each and fasted for 48 hours previousto the experiments, water being available ad libitum. The animals wereanesthetized with ether, the abdomen opened through a midline incision,and the pylorus ligated. Test compounds were diluted from stock solutionso as to administer a dose of 1.5 mg/kg in a volume equivalent to 1ml/kg. Subcutaneous injections were applied immediately after surgeryand again 2 hours later, so that a total dose of 3.0 mg/kg wasadministered. Dilutions were made with phosphate buffer (pH 7.38) asrecommended by Lee et al. (Prostaglandins, 3: 29 [1973]) in order toinsure adequate stability of drugs at the subcutaneous depot. Eachcompound was tested in one group of rats; an additional control groupreceived only the vehicle.

Four hours after pyllric ligation the animals were killed with ether,the cardias ligated, and the stomachs removed. The volume of gastricsecretion was measured and the contents centrifuged at 5000 rpm for 10minutes. Total acid in the supernatant was titrated against a 0.1Nsodium hydroxide solution and the amount expressed in mEq.

Volume and total acid values of the treated group were compared withthose of the controls of the t-test. Antisecretory activity was scoredaccording to the following scale:

    ______________________________________                                        % decrease in acidity                                                                          Activity Value                                               ______________________________________                                        <26              0                                                            26-50, not significant                                                                         1                                                            26-50, significant                                                                             2                                                            51-75            3                                                            76-100           4                                                            ______________________________________                                    

G. Evaluation of the Effects on Blood Pressure and Heart Rate in theAnesthetized Cat

The acute effects of test compounds on blood pressure and heart ratewere determined in cats of either sex anesthetized with a mixture ofpentobarbital sodium (35 mg/kg, i.v.) and barbital sodium (100 mg/kg,i.v.). Cannulas were placed in the trachea to allow adequate spontaneousventilation, in a femoral artery for blood pressure recording with astrain gage transducer, and in a saphenous vein for drug administration.Heart rate was recorded by means of a cardiotachometer driven by the Rwave of the electrocardiogram. After a period of 10 minutes of stablerecordings of blood pressure and heart rate, the test compound wasadministered intravenously at doses increasing from 0.01 to 10.0 mcg/kg,spaced one log and injected at 10 minute intervals. All doses wereinjected in a volume of 0.1 ml/kg. Modifications of blood pressure andheart rate induced by the test compound were expressed both in absoluteunits (mmHg and beats/minute) and as percent of values recordedimmediately before administration of each dose. Biphasic responses weretabulated in the order in which they occurred. The direction of theobserved changes is also noted (+ for increases, and - for decreases).

Activity of compounds in this test was judged only on the basis of thedegree of hypotension observed. Thus, the ED₅₀ mmHg (dose decreasingblood pressure by 50 mmHg) was calculated graphically, and the compoundscored according to the following scale:

    ______________________________________                                        ED.sub.50 mmHg, mcg/kg                                                                         Activity Value                                               ______________________________________                                        >10.0            0                                                             1.01-10.0       1                                                            0.11-1.0         2                                                            0.01-0.1         3                                                            <0.01            4                                                            ______________________________________                                    

H. Evaluation of Effects on Femoral Blood Flow in the Anesthetized Dog

The peripheral vasodilator or constrictor effects of test compounds weredetermined in mongrel dogs of either sex, weighing between 10 and 20 kg,anesthetized intravenously with 35 mg/kg of pentobarbital sodium. Anexternal iliac artery was dissected immediately above the femoral archfor a length of approximately 5 cm, and a previously calibarated,non-cannulating electromagnetic-flowmeter sensor with a lumen between2.5 and 3.5 mm was placed snugly around the vessel. Cannulas were placedin a branch of the artery arising distally to the location of theflowmeter sensor for intraarterial drug administrations, in thecontralateral femoral artery for systemic blood pressure recording, andin the trachea for artificial respiration with room air. Femoral bloodflow and systemic blood pressure were continuously recorded with anelectromagnetic flowmeter and pressure transducer, respectively.

After an adequate control period, test compounds were injectedintraarterially at one log-spaced doses ranging from 0.001 to 10 mcg, ina volume of 0.5 ml and at 5 to 10 minute intervals. Maximum changes inblood flow, as well as any variations in blood pressure, were tablulatedfor each dose in absolute values (ml/min. and mmHg), and the former werealso expressed in percent. Those calculations were made taking ascontrol values those existing immediately before administration of eachdose. The direction of the observed change (+ for increase and - fordecrease) was also noted. The dose changing blood flow by 100 ml/min(ED₁₀₀ ml/min) was calculated graphically and was used for scoringactivity as follows:

    ______________________________________                                        ED.sub.100 ml/min. mcg                                                                        Activity Value                                                ______________________________________                                        >10.0           0                                                              1.01-10.0      1                                                             0.11-1.0        2                                                             0.0-0.1         3                                                             <0.01           4                                                             ______________________________________                                    

I. Evaluation of the Effects on Blood Pressure in the Hypertensive Rat

The acute anithypertensive activity of test compounds was determined inrats made hypertensive by the procedure of Grollman (Proc. Soc. ExperBiol. Med., 57: 102 [1944]). Female rats weighing between 60 and 100 gwere anesthetized with ether, the right kidney approached through aflank retroperitoneal incision, decapsulated and tied with afigure-of-eight-ligature. The animals were left to recover and two weekslater were again anesthetized and the contralateral kidney removed. Fourweeks after the second operation the rats were subjected to indirectblood pressure measurements and those showing systolic pressure valuesgreater than 160 mmHg were selected for drug testing.

Blood pressure was measured in the tail with an inflatable occludingcuff placed at the base of the extremity and a pulse detector locateddistally. The cuff was inflated to approximately 300 mmHg and was slowlydeflated until pulsations appeared, indicating the level of systolicpressure; diastolic pressure was not recorded by this procedure. Allmeasurements were carried out in unanesthetized, unsedated animalsmaintained in a warm environment during the recording procedure and forat least 6 hours before. In all cases, three pressure readings wereobtained in succession and mean values were calculated thereof.

Experiments were carried out in groups of five hypertensive rats inwhich systolic pressure was determined immediately before and 2, 4, 6and 9 hours after intraperiotoneal administration of the test compoundat a dose of 1 mg/kg. Drugs were diluted from stock solutions withphosphate buffer (Lee et. al., Prostaglandins, 29 [1973]), so as toinject this quantity in a volume of 1 ml/kg. Changes from control bloodpressure values were calculated for each interval both in mmHg and inpercent, and evaluated for significance by means of Wilcoxon's signedrank test (Wilcoxon, R. and Wilcox, R. A., "Some Rapid ApproximateStatistical Procedures", Lederle Laboratories, Pearl River [1964]).Activity of the compound was scored as follows:

    ______________________________________                                        Blood pressure decrease                                                                            Activity Value                                           ______________________________________                                        Not significant at any time interval                                                               0                                                        Significant at one time interval                                                                   1                                                        Significant at two time intervals                                                                  2                                                        ______________________________________                                    

As earlier discussed, the Searle prior art discloses the methyl esteranalogous to presently claimed TR 4698 and TR 4706. Searle contains noexperimental data or examples to support the alleged utility ofinhibition of gastric secretion without the "undesirable side-affectsdispayed by related substances." The acid and ester analogues arefurther alleged to be inhibitors of blood platelet aggregation and todisplay anti-fertility and bronchodilating properties.

The Lederle prior art discloses the methyl ester of presently claimed TR4752 and TR 4749. Lederle alleges utility of the acid and esteranalogues as agents for the "treatment of gastric hypersecretion andgastric erosia" and as bronchodilators. Anti-ulcer, gastricantisecretory and bronchodilator properties are given for 16-hydroxyacid analogues, 9-oxo-10-hydroxy-13-prostanoic acid and9-oxo-16-hydroxy-13-trans-prostanoic acid.

The experimental test data summarized in Table G demonstrates thenonobviousness of the claimed alkyl-substituted PGE₁ carbinol analoguesover the Searle and Lederle ester and acid analogues. Examples 1-4demonstrate that the alkyl-substituted carbinols of the presentinvention have an unexpected clean separation of biological activity, incomparison with the corresponding acid and ester analogues.

                                      TABLE G                                     __________________________________________________________________________                                  Feline                                                                        Blood     Blood              Plate-             Exam-                                                                             TR  Cascade      Rat Guinea                                                                             Pressure,                                                                          Femoral                                                                            Pressure                                                                            Gastric      let                ple Num-                                                                              Stom-                                                                             Co-                                                                              Rec-                                                                             Aor-                                                                             Uter-                                                                             Pig  Heart                                                                              Blood                                                                              Hyperten-                                                                           Secre-                                                                            Antagonism                                                                             Aggre-             No. ber ach lon                                                                              tum                                                                              ta us  Trachea                                                                            Rate Flow sive Rat                                                                            tion                                                                              PGE1                                                                              PGF2A                                                                              gation             __________________________________________________________________________    1   4698                                                                              0   1  1  0  --  R4   0    0    1     4   0   0    +0                 Comp.                                                                             4704                                                                              2   1  2  0  --  R3   2    3    0     4   0   0    +0                 2   4706                                                                              1   1  1  0  --  R2   0    0    0     4   1   1    +0                 Comp.                                                                             4705                                                                              2   1  2  0  --  R2   0    1    0     4   1   1    +0                 B                                                                             3   4752                                                                              0   0  0  0  0   R4   0    0    0     0   0   0    +0                 Comp.                                                                             4836                                                                              0   0  0  0  0   R4   --   --   --    4   0   0    +1                 C                                                                             4   4749                                                                              0   0  0  0  0   R2   0    0    0     3   0   0    +0                 Comp.                                                                             4814                                                                              0   0  0  0  0   R4   0    2    1     4   0   0    +0                 D                                                                             __________________________________________________________________________

The gastric anisecretory (GAS) and guinea pig trachea values for TR 4698and its methyl ester analogue TR 4704 are the same. However, the felineblood pressure and heart rate, femoral blood flow and cascade values aresignificantly and undesirably higher for the methyl ester analogue. Thecarbinol analogue shows a significantly cleaner separation of biologicalactivity, that is, a greater reduction of undesirable side-effects thenthe methyl ester analogue.

Similarly, the GAS and guinea pig trachea values for TR 4706 and itsmethyl ester analogue TR 4705 are the same. The femoral blood flow forthe TR 4705 analogue is slightly higher than the TR 4706 value; thestomache and colon values for the cascade are higher for the TR 4705 incomparison to TR 4706, indicating that TR 4706 shows a significantlycleaner separation of biological activity.

The biological activity of TR 4752 and its methyl ester analogue TR 4836are similar. However, TR 4752 shows no GAS activity, indicatingusefulness of TR 4752 for a single indication, tracheal relaxation.

The GAS and guinea pig trachea values for TR 4749 are both lower thanthe values for its methyl ester analogue. The femoral blood flow andhypertensive rat blood pressure are both higher for the methyl esterthan the carbinol, indicating that TR 4749 shows a significantly cleanerseparation of biological activity.

Experimental test data values, for the compounds of Examples 5-16 arelocated in Table H.

                                      TABLE H                                     __________________________________________________________________________                                  Feline                                                                        Blood     Blood              PLate-             Exam-                                                                             TR  Cascade      Rat Guinea                                                                             Pressure,                                                                          Femoral                                                                            Pressure                                                                            Gastric      let                ple Num-                                                                              Stom-                                                                             Co-                                                                              Rec-                                                                             Aor-                                                                             Uter-                                                                             Pig  Heart                                                                              Blood                                                                              Hyperten-                                                                           Secre-                                                                            Antagonism                                                                             Aggre-             No. ber ach lon                                                                              tum                                                                              ta us  Trachea                                                                            Rate Flow sive Rat                                                                            tion                                                                              PGE1                                                                              PGF2A                                                                              gation             __________________________________________________________________________     5  4840                                                                              0   0  0  0  0   R0   --   --   --    0   0   0    +1                     4848                                                                              0   0  0  0  0   R1   --   --   --    0   0   0    +1                  6  4844                                                                              0   0  0  0  0   C0   --   --   --    0   0   0    +1                     4846                                                                              0   0  0  0  0   R0   --   --   --    1   0   0    +1                  7  4703                                                                              0   0  0  0  0   R2   0    0    0     0   0   0    +1                  8  4753                                                                              0   0  0  0  0   R2   --   --   --    0   0   1    +1                  9  4851                                                                              0   0  1  0  0   R3   0    --   0     0   0   0    +1                 10  4770                                                                              0   0  1  0  0   R3   0    0    --    3   0   0    +1                 11  4803                                                                              0   0  0  0  0   R4   --   --   --    1   0   0    +1                 12  4804                                                                              0   0  0  0  0   R0   --   --   --    0   1   1    +1                     4806                                                                              0   0  0  0  0   C0   --   --   --    0   0   0    +1                 13  4799                                                                              0   0  0  0  --  R4   --   --   0     0   0   0    --                     4805                                                                              0   0  0  0  0   R0   --   --   --    0   0   0    +1                 14  4903                                                                              0   0  0  0  0   R3   --   --   --    2   0   0    +1                 15  4982                                                                              --  -- -- -- --  R1   --   --   --    1   --  --   +1                     4983                                                                              --  -- -- -- --  R2   --   --   --    1   --  --   +1                 16  4984                                                                              0   0  0  -- --  R0   --   --   --    0   --  --   +1                     4985                                                                              0   0  0  -- --  R1   --   --   --    0   --  --   +1                 __________________________________________________________________________

The following ester prostaglandin analogues, containing a cycloalkyl,bicycloalkyl or bicycloalkenyl moiety, were prepared as described below.

EXAMPLE 17 Methyl 15R, 19-cyclo-11α,16-trans-dihydroxy-20-nor-9-oxoprost-13E-en-1-oate and Methyl 15S,19-cyclo-11α, 16-trans-dihydroxy-20-nor-9-oxoprost-13E-en-1-oate (TR4838 and TR 4839) A. Preparation of Iodovinyl Alcohol

A solution of 4.0 g of commercially available cyclopentene oxide and 30ml of hexamethylphosphoramide (HMPA) was stirred under argon at 25°.Commercially available lithium acetylide ethylene diamine complex (5.6g) was added and the reaction mixture heated at 80° for two hours. Thereaction mixture was cooled to 0° and 20 percent aqueous ammoniumchloride added. The mixture was extracted with ether. The extracts werewashed with 10 percent HCl, water (five times), saturated aqueous NaHCO₃and brine, then dried, filtered, and distilled using aspirator vacuum toyield 2.15 g trans-2-ethynylcyclopentan-1RS-ol, bp 72°. The product hadthe following spectral characteristics: nmr (CDCl₃) δ 1.0 to 3.0 (9H, m)and 4.25 ppm (1H, m); ir (CHCl₃) 860, 900, 995, 1080, 1215, 1450, 2110,2860, 2960, 3300, 3200-3600 (broad) and 3600 cm⁻¹.

The trans-2-ethynylpentan-1RS-ol was converted to the correspondingiodovinylalcohol, trans-2-(2E-iodoethenyl)cyclopentan-1RS-ol asdescribed below.

A 130 ml portion (150 mmol) of a solution of (1.15M) diisobutylaluminumhydride in dry toluene was stirred under argon with ice water bathcooling as a second solution of 5.24 g (52.4 mmol) of thetrans-2-enthynylcyclopentan-1RS-ol, in 10 ml of dry toluene was addeddropwise over a period of one hour. Stirring was then continued withoutcooling for one hour and then with oil bath warming (60° C.) for threehours. The oil bath was then replaced with a dry ice-acetone (-78° C.)bath as a third solution of 26.8 g (105 mmol) of iodine in drytetrahydrofuran to total 100 ml was added dropwise to the reactionmixture maintaining a stirring of the reaction mixture. The cooling bathwas then removed and the reaction mixture was allowed to come to 20°slowly before it was quenched by being forced under a slight argonpressure through polyethylene tubing into a vigorously stirred mixtureof ether and two percent aqueous sulfuric acid. The ether phase wasremoved and then washed successively with another portion of two percentsulfuric acid, brine, saturated aqueous sodium bicarbonate and brine. Itwas dried over Na₂ SO₄ and evaporated under reduced pressure. Theresidue (6.36 g) was distilled at high vacuum to remove the mostvolatile contaminants. The iodovinylalcohol remained undistilled at 560and was used as is.

The iodovinyl alcohol had the following spectral characteristics: nmr(CDCl₃) δ 0.8-2.7 (8H, m), 3.85 (1H, broad m), 6.10 (1H, d, J=41 Hz) and6.50 (1H, d of d, J=14, 7 Hz); ir (CHCl₃) 870, 910, 860, 1040, 1080,2870, 2940, 3200-3600 (broad) and 3580 cm⁻¹.

B. Preparation of Organolithiocuprate from Iodovinylalcohol (1)Preparation oftrans-2-(2E-iodoethenyl)-1RS-(tetrahydropyranyloxy)cyclopentane

The hydroxyl function of the above iodovinylalcohol was protected asdescribed below.

A mixture of 4.8 g (2.02 mmol) oftrans-2-(2E-iodoethenyl)cyclopentan-1RS-ol 3.7 ml dihydropyran and a 20mg portion of toluenesulfonic acid in 1.5 ml of dry ether was stirred ina flask under argon. After 18 hours, the product solution was washedwith aqueous NaHCO₃ solution. The wash solution was back-extracted withether and the extracts combined. The combined extract was dried (Na₂SO₄) and evaporated in vacuo to yield 7.2 g of residue which waschromatographed on silica gel 60 using chloroform elution. The yield ofpure protected iodovinylalcohol was 3.2 g. The iodovinyl alcohol had thefollowing spectral characteristics: nmr (CDCl₃) δ 0.8-2.3 (13H, m)3.2-4.2 (3H, m), 4.65 (1H, broad s), and 5.9 to 6.8 ppm (2H, m); ir(CHCl₃) 865, 910, 975, 1030, 1075, 1130, 2880 and 2960 cm⁻¹.

(2) Preparation of Organolithiocuprate from Protected Iodovinylalcohol

A solution of 0.715 g (2.2 mmol) oftrans-2-(2E-iodoethyl)-1RS-(tetrahydropyranyloxy)cycloptentane in 12 mlof dry ether was stirred in a flask under argon with -78° bath coolingas 4.2 ml (4.4 mmol) of a 1.1M solution of t-butyllithium in pentane wasadded, dropwise via syringe. The resultant solution was left to stir at-78° for two hours.

A second solution was prepared by stirring under argon a suspension of0.275 g (2.1 mmol) of dry copper (I) pentyne in 5.1 ml of dry ethersolubilized with 0.84 ml of hexamethylphosphorous triamide, until itbecame homogeneous. This first solution was then transferred viapolyethylene tubing to the above coper(I)pentyne solution as it wasstirred with -78° bath cooling. The desired lithiocuprate reagent, anorange mixture, was stirred 30 minutes after addition was complete.

C. Substituted 2-Cyclopenten-1-one

4R-(tetrahydropyran-2-yloxy)-2-(6-carbomethoxyhexyl)cyclopent-2-en-1-onewas prepared as described by C. J. Sih et al., J. Amer. Chem. Soc., 97,865 (1975).

D. Prostaglandin Synthesis

The synthesis of the prostaglandin E₁ analogue was achieved as describedbelow.

A solution of 0.650 g of the above substituted cylcopent-2-en-1-one in7.6 ml of dry ether was added dropwise to the lithiocuprate reactionmixture as stirring was continued at -78°. After addition was complete,the resultant orange mixture was stirred for 30 minutes at -78° then at-20° for 1.5 hours, and then at 0° for 1.5 hours.

The reaction was quenched by addition of 20 percent aqueous ammoniumsulfate and the aqueous layer extracted with ether. The combined organiclayers were washed with 2 percent aqueous sulfuric acid and filteredthrough celite. The filtrate was washed with saturated aqueous sodiumbicarbonate and brine, then dried (MgSO₄), filtered and evaporated invacuo to yield 1.1 g of residue containing the tetrahydropyran-protectedform of TR 4838.

This residue was dissolved in 50 ml of acetic acid-water-tetrahydrofuran(65:35:10) and left to stand under argon for 18 hours at roomtemperature and the resultant solution evaporated in vacuo to remove thesolvent. The residue was dissolved in ethyl acetate and washed withsaturated aqueous sodium bicarbonate. The wash solution was backextracted with ethyl acetate. The combined extract was dried over MgSO₄and evaporated in vacuo to yield 525 mg of a yellow residue. Thisresidue was chromatographed on silicic acid-diatomaceous earth (85:15)using benzene-ethyl acetate.

Chromatography of the crude product yielded: Methyl 15R, 19-cyclo-11α,16-trans-dihydroxy-20-nor-9-oxoprost-13E-en-1-oate and Methyl 15S19-cyclo-11α, 16-trans-dihydroxy-20-9-oxoprost-13E-en-1-oate PGE₁analogues having the following spectral characteristics:

More Polar Isomer (TR 4839)-[α]_(D) -83.1° (c 1.02, CHCl₃); R_(f)(system II) 0.31; nmr (CDCl₃) 1.0-3.0 (24H, m), 3.67 (3H, s), 3.5-4.2(4H, m), and 5.43 ppm (2H, m); ir (CHCl₃) 910, 970, 1090, 1180, 1230,1370, 1450, 1740, 2860, 2930 and 3100-3600 cm⁻¹ ; ms (70 eV) m/e 352(p), 334, 316, 306, 302.

Less Polar Isomer (TR 4838)-[α]_(D) -36.5° (c 0.88, CHCl₃); R_(f)(system II) 0.37; nmr, ir and ms were much the same as those for thepolar isomer above.

EXAMPLE 18 Methyl 15R, 20-cyclo-11α,16-trans-dihydro-9-oxoprost-13E-en-1-oate and Methyl 15S, 20-cyclo-11α,16-trans-dihydro-9-oxoprost-13E-en-1-oate (TR 4767 and TR 4768)

The cyclopentene oxide of Example 17 was replaced with commerciallyavailable cyclohexene oxide. The procedure of Example 17 was followed toconvert the cyclohexene oxide into the corresponding acetylenic alcohol,(I)-trans-2-ethynylcyclohexanol. The acetylenic alcohol had thefollowing spectral characteristics: nmr (CDCl₃) δ 0.8-2.5 (10H, m), 2.58(1H, broad s) and 3.55 (1H, broad m); ir (CHCl₃) 840, 1010, 1070, 1110,1270, 1450, 2110, 2860, 2950, 3300, 3200-3600 (broad) and 3575 cm⁻¹.

The acetylenic alcohol was converted into the corresponding iodovinylalcohol and the protected iodovinyl alcohol as described in Example 15.The (±)-trans-2-ethynylcyclopentene of Example 15 was replaced with(±)-trans-2-ethynylcyclohexanol; the following change was made in theprocedure. When the iodine solution was added to the reaction mixture,it was added only until color persisted for one minute or more. Productisolation proceeded as in Example 1. The iodivinyl alcohol,(±)-trans-2-(2E-iodoethenyl)cyclohexanol had the following spectralcharacteristics: nmr (CDCl₃) 0.8-2.3 (10H, m), 3.3 (1H, broad m), 6.13(1H, d, J=14 Hz) and 6.50 Hz (1H, d of d, J=14 Hz).

The tetrahydropyranyloxy-protected iodovinyl alcohol,(±)-trans-2-(2E-iodoethenyl)-1RS-(tetrahydropyranyloxy)cyclohexane, hadthe following spectral characteristics: nmr (CDCl₃) δ 0.8-2.2 (15H, m),3.2-4.2 (3H, m), 4.5 (1H, broad s), 6.02 (1H, d, J=14 Hz) and 6.53 ppm(1H, d of t, J=14, 7 Hz); ir (CHCl₃) 860, 900, 980, 1020, 1075, 1120,1360, 1450, 1610, 2850, and 2950 cm⁻¹.

The synthesis of the PGE₁ methyl ester analogues was carried out asdescribed in Example 17. Chromatography of the the crude product yieldedisomers, methyl 15R and S, 20-cyclo-11α, 16R and Sdihydroxy-9-oxoprost-13E-en-1-oate. The physical characteristics of theisomers were:

More Polar Isomer (TR 4768)-[α]_(D) -81.5° (c 0.72, CHCl₃); R_(f)(system II) 0.25; nmr (CDCl₃) δ 0.8-3.0 (25H, m), 3.0-4.2 (4H, m), 3.63(3H, s) and 5.40 ppm (2H, m); ir (CHCl₃) 900, 970, 1090, 1160, 1240,1740, 2860, 2940 and 3100-3600 cm⁻¹ ; ms (70 eV) m/e 366 (p), 348, 330.

Less Polar Isomer (TR 4767)-[α]_(D) +3.3° (c 1.0, CHCl₃); R_(f) (systemII) 0.32; nmr, ir and ms similar to those of the polar isomer above.

EXAMPLE 19 Methyl 11α, 16RS-dihydroxy-16,20-methano-9-oxoprost-13E-en-1-oate (TR 4717)

A 12.2 g portion of magnesium turnings was heat dried under argon in a500 ml flask fitted with an air stirrer, condensor and addition funnel.After cooling the flask, 60 ml of dry ether was added, followed by asmall portion of a solution of 33.9 ml of propargyl bromide in 60 ml ofdry ether followed by 50 mg of mercuric chloride. After spontaneousether reflux indicated that the reaction had commenced, the remainder ofthe propargyl bromide solution was added dropwise to the mixture tomaintain gentle reflux. After the addition was complete, the reactionmixture was stirred for an additional one-half hour. A solution of 27 gof cyclohexanone, commercially available, in 25 ml of dry ether was thenadded to the reaction mixture, again at a rate to maintain gentlereflux. A heated oil bath was then used to reflux the final mixture foranother hour. The final mixture was then quenched by the addition ofwater, followed by 10 percent hydrochloric acid to dissolve solid salts.The phases were separated and the ether extract was washed with brineand saturated sodium bicarbonate solution. It was then dried over MgSO₄and then distilled using a water pump to successively remove ether and atrace of cyclohexanone (bp ca 50°). The 1-(prop-2-ynyl)cyclohexanol (bp91°-94° ) had the following spectral characteristics: nmr (CDCl₃) δ1.0-2.0 (10H, m), 2.0-2.2 (2H, m), and 2.39 ppm (2H, m); ir (CHCl₃) 870,980, 1060, 1150, 1270, 1450, 1220 (weak), 2860, 2930, 3300, 3200-3600(broad) and 3570 cm⁻¹.

The 1-(prop-2-ynyl)cyclohexanol was converted to the correspondingidovinylalcohol, 1-(3-iodoprop-2E-enyl)cyclohexanol as described below.

A solution of 30 ml (169 mmol) of diisobutylaluminum hydride in 75 ml ofdry toluene was stirred under argon with ice water bath cooling as asecond solution of 7.0 g (50 mmol) of the 1-(prop-2-ynyl)cyclohexanol,in 25 ml of dry toluene was added dropwise over a period of one hour.Stirring was then continued without cooling for one hour and then withoil bath warming (50°-60° C.) for three hours. The oil bath was thenreplaced with a dry ice-acetone (-78° C.) bath as a third solution of42.8 g (169 mmol) of iodine in dry tetrahydrofuran to total 100 ml wasadded dropwise to the reaction mixture maintaining a stirring of thereaction mixture. The cooling bath was then removed and the reactionmixture was allowed to come to 20° slowly before it was quenched bybeing forced under a slight argon pressure through polyethylene tubinginto a vigorously stirred mixture of ether and two percent aqueoussulfuric acid. The ether phase was removed and then washed successivelywith another portion of two percent sulfuric acid, brine, saturatedaqueous sodium bicarbonate and brine. It was dried over Na₂ SO₄ andevaporated under reduced pressure. The residue (10.3 g) waschromatographed on silica gel to yield 0.54 g of the pure iodovinylalcohol.

The iodovinyl alcohol had the following spectral characteristics: bp83°-85° (0.1 nmr (CDCl₃) δ 1.0-1.8 (11H, m), 2.22 (2H, d, J=6 Hz), 6.16(1H, d, J=14 Hz) and 6.76 ppm (1H, d of t, J=14, 7 Hz); ir (CHCl₃) 905,950, 1140, 1455, 1610, 2870, 2950, 3200-3600 (broad) and 3600 cm⁻¹.

Because of the low yield, an alternate procedure was used to prepareadditional iodovinyl alcohol compound (as the hydroxyl-protected form).

A solution of 2.9 g (21 mmol) of 1RS-(prop-2-ynyl)cyclohexanol in 10 mlof dry ether was stirred under argon as 0.24 ml (26 mmol) ofdihydropyran was added followed by a small scoop (ca. 5 mg) oftoluenesulfonic acid. After one hour tlc (CHCl₃, silica gel) analysisindicated that significant starting material remained so another 0.2 mlof dihydropyran and a small scoop of toluenesulfonic acid were added.Twice more at one hour intervals 0.2 ml portions of dihydropyran and atrace of toluenesulfonic acid were added to the reaction mixture. It wasfinally left to stir under argon at room temperature for 15 hours.Potassium carbonate was then added to the mixture and it was stirred forseveral minutes before it was washed with water. The wash solution wasback extracted with ether and the combined extracts were then washedwith brine, dried (Na₂ SO₄) and evaporated in vacuo to yield 4.6 g of1-(tetrahydropyran-2-yloxy)-1-(prop-2-ynyl)cyclohexane having thefollowing spectral characteristics: nmr (CDCl₃) δ 1.0-2.5 (19H, m), 3.6(2H, broad m) and 4.65 ppm (1H, broad s); ir (CHCl₃) 980, 1030, 1050,1070, 1120, 1150, 1270, 1450, 2120, (weak), 2760, 2930, and 3300 cm⁻¹.

The alternate procedure was carried out as described below.

A 200 ml portion of 1M borane in tetrahydrofuran was stirred under argonwith -10° bath cooing in a flask fitted with a dry ice condensor. Atotal of 46 ml (400 mmol) of 2-methyl-2-butene was then added slowly viasyringe below the surface of the borane solution. The reaction mixturewas then stirred one hour at 0° and then left overnight in arefrigerator.

A 10 ml portion of the above disiamylborane solution was stirred underargon with ice bath cooling as 2.4 g of1-(tetrahydroryran-2-yloxy)-1-(prop-2-ynyl)cyclohexane was added slowly.The resultant solution was stirred at room temperature for two hours.Tlc (CHCl₃, silica gel) showed that the reaction was not complete. Asecond 10 ml portion of disiamylborane solution was added to thereaction mixture. After another 1.5 hours the reaction was quenched bythe addition of 3.3 g of trimethylamine oxide dihydrate portionwise over30 minutes. The resultant mixture was stirred (still at 0°) for onehour. A 33 ml portion of 1M aqueous sodium hydroxide was then addedquickly followed by a solution of 7.6 g of iodine in 40 ml of drytetrahydrofuran. The resultant mixture was stirred one hour without acooling bath and then poured into 100 ml of water. Sodium thiosulfatewas then added until the color of excess iodine had dissipated. Theresultant mixture was extracted with ether. The extract was washed withwater and then brine. It was evaporated in vacuo to yield 9.00 ofresidue. This residue was dissolved in methanol and benzene which werethen removed by evaporation in vacuo to yield 5.0 g of residue. Thisresidue was chromatographed on silica gel using chloroform elution toyield 2.4 g of pure1-(3-iodoprop-2E-enyl)-1-(tetrahydropyranyloxy)cyclohexane. The spectralproperties of this material were identical to those of the materialprepared by the earlier procedure.

The methods described in Example 17 were used to prepare TR 4717 byreplacingtrans-2-(2E-iodoethyl)-1RS-(tetrahydropyran-2-yloxy)cyclopentane with1-(3-iodoprop-2E-enyl)-1-(tetrahydropyran-2-yloxy)cyclohexane.

The resulting PGE₁ analogue TR 4717 had the following spectralcharacteristics:

[α]_(D) -68.4° (c 1.0, CHCl₃); R_(f) (system II) 0.47; nmr (CDCl₃) δ1.0-3.0 (29H, m), 3.56 (2H, broad s), 3.70 (3H, s), 4.08 (1H, m) and5.63 (2H, m); ir (CHCl₃) 885, 970, 1080, 1170, 1245, 1360, 1425, 1740,2860, 2930 and 3200-3600 cm⁻¹ ; ms (70 eV) m/e 368, 362, 344, 312, 282,264, 232, 204.

EXAMPLE 20 Methyl11α,16RS-dihydroxy-16,18-methano-17,20-methano-9-oxoprosta-13E,19-dien-1-oate and Methyl16RS-hydroxy-16,18-methano-17,20-methano-9-oxoprosta-10,13E,19-trien-1-oate (TR 4800 and TR 4802)

The method described in Example 19 was used to prepare TR 4800 and 4802by replacing the cyclohexanone with bicyclo[3.2.0]hept-2-en-6-one. Thebicyclo starting material was produced as described in TetrahedronLetters 307 (1970).

The procedure of Example 19 was followed to obtain the correspondingacetylenic alcohol, the corresponding iodovinyl alcohol and thecorresponding protected iodovinyl alcohol.

The acetylenic alcohol had the following spectral characteristics: nmr(CDCl₃) δ 1.5-3.2 (10H, m) and 5.83 (2H, m); ir (CHCl₃) 690, 930, 1170,1260, 1350, 1415, 2120 (weak), 2850, 2930, 3300, 3200-3600 (broad) and3570 cm⁻¹.

The 6-(3-iodoprop-2E-enyl)bicyclo[3.2.0]hept-2-en-6RS-ol had thefollowing spectral characteristics: nmr (CHCl₃) δ 1.5-3.2 (9H, m), 5.82(2H, m), 6.10 (1H, d, J=14 Hz) and 6.59 ppm (1H, d of t, J=14, 7 Hz).

The6-(3-iodoprop-2E-enyl)-6RS-(tetrahydropyranyloxy)bicyclo[3.2.0]hept-2-enehad the following spectral characteristics: nmr (CDCl₃) δ 1.2-3.0 (14H,m), 3.2-4.2 (2H, m), 4.60 (1H, broad s), 5.77 (2H, broad s), 6.08 (1H,d, J=14 Hz) and 6.60 ppm (1H, d of t, J=14, 7 Hz); ir (CHCl₃) 870, 910,990, 1030, 1075, 1130, 1610, 2860, and 2950 cm⁻¹.

The synthesis of the PGE₁ analogue (TR 4800) was carried out asdescribed in Example 19. A small amount of PGA₁ prostaglandin analogue(TR 4802) was produced as a side-product. The prostaglandin analogueshad the following spectral characteristics:

TR 4800-[α]_(D) -56.1° (c 1.0 CHCl₃); R_(f) (system II) 0.39; nmr(CDCl₃) δ 1.0-3.2 (26H, m), 3.66 (3H, s), 4.0 (1H, m), and 5.4-6.0 ppm(4H, m); ir (CHCl₃) 970, 1070, 1160, 1240, 1350, 1440, 1730, 2860, 2740and 3200-3600 cm⁻¹ ; ms (70 eV) m/e 390 (p), 372, 358, 340, 324, 306,292, 274, 232.

TR 4802-[α]_(D) +67.4° (c 1.0, CHCl₃); R_(f) (system II) 0.62; nmr(CDCl₃) δ 1.0-3.2 (22H, m), 3.23 (1H, m), 3.64 (3H, s), 5.59 (2H, m),5.81 (2H, m), 6.14 (1H, m) and 7.48 ppm (1H, m); ir (CHCl₃) 970, 1030,1170, 1220, 1350, 1440, 1710, 2860, 2930 and 3200-3600 cm⁻¹ ; ms (70 eV)m/e 372 (p), 340, 323, 306, 274, 232.

EXAMPLE 21 Methyl11α,16RS-dihydroxy-17,20-ethano-16,18-methano-9-oxoprost-13E-en-1-oateand Methyl17,20-ethano-16RS-hydroxy-16,18-methano-9-oxoprosta-10,13E-dien-1-oate(TR 4808 and TR 4807)

A solution of bicyclo[4.2.0]octan-7-one was substituted for thecyclohexanone of Example 19. The bicyclo[4.2.0]octan-7-one was preparedfrom bicyclo[4.2.0]oct-2-en-7-one. The bicyclo[4.2.0]oct-2-en-7-one wasprepared as described in Tetrahedron Letters 4753 (1971).

The bicyclo[4.2.0]oct-2-en-7-one had the following spectralcharacteristics: nmr (CDCl₃) 1.5-2.5 (8H, m), 2.03 (1H, t, J=2.5 Hz)2.35 (1H, s) 2.55 (2H, d, J=2.5 Hz) and 5.72 ppm (2H, m); ir (CHCl₃)880, 1000, 1120, 1270, 1445, 2130 (weak), 2850, 2950, 3310, 3200-3600(broad) and 3570 cm⁻¹.

The bicyclo[4.2.0]oct-2-en-7-one compound was converted intobicyclo[4.2.0]octan-7-one as follows.

A solution of 4.2 g of bicyclo[4.2.0]oct-2-en-7-one in isopropanol,total solution of 100 ml, was hydrogenated over 0.5 g of platinum oxideat 50 PSI of hydrogen in a Parr shaker for 18 hours. The catalyst wasremoved by filtration and the filtrate was evaporated to yield 3.2 g ofthe compound, having the following spectral characteristics: nmr 0.8 to3.5 ppm (m); ir 1040, 1090, 1450, 1765, 2860 and 2930 cm⁻¹.

The procedure of Example 19 was followed to obtain the correspondingacetylenic alcohol, the corresponding iodovinyl alcohol and thecorresponding protected iodovinyl alcohol by replacing cyclohexanonewith bicyclo[4.2.0]octan-7-one. The7-(prop-2-ynyl)bicyclo[4.2.0]octan-7RS-ol had the following spectralcharacteristics: nmr (CDCl₃) δ 1.0-2.2 (13H, m), 2.28 (1H, s) and 2.47ppm (2H, d, J=2.5 Hz); ir (CHCl₃) 900, 1070, 1140, 1260, 1460, 2120(weak), 2860, 2930, 3300, 3200 to 3600 (broad) and 3570 cm⁻¹.

The 7-(3-iodoprop-2E-enyl)bicyclo[4.2.0]octan-7RS-ol had the followingspectral characteristics: nmr (CDCl₃) δ 1.0-2.2 (13H, m), 2.37 (2H, d,J=6 Hz), 6.10 (1H, d, J=14 Hz) and 6.72 ppm (1H, d of t, J=14, 7 Hz); ir(CHCl₃) 905, 950, 1075, 1100, 1130, 1260, 1455, 1610, 2850, 2930,3200-3600 (broad) and 3600 cm⁻¹.

The iodovinyl alcohol was protected to yield7-(3-iodoprop-2E-enyl)-7RS-(tetrahydropyranyloxy)bicyclo[4.2.0]octanehaving the following spectral characteristics: nmr (CDCl₃) δ 0.8-2.6(20H, m), 3.2-4.2 (2H, m), 4.57 (1H, broad s), 6.02 (1H, d, J=14 Hz) and6.3-6.9 (1H, m); ir (CHCl₃) 870, 945, 1020, 1070, 1120, 1270, 1450, 2850and 2940 cm⁻¹.

The synthesis of the PGE₁ analogue (TR 4808) was carried out asdescribed in Example 15. A small amount of the PGA₁ prostaglandinanalogue (TR 4807) was produced as a side-product. The prostaglandinanalogues had the following spectral characteristics:

TR 4808-[α]_(D) -56.3° (c 1.0, CHCl₃); R_(f) (system II) 0.42; nmr(CDCl₃) δ 1.0-3.0 (30H, m), 3,39 (2H, broad s), 3.65 (3H, s), 4.04 (1H,m) and 5.60 ppm (2H, m); ir (CHCl₃) 970, 1010, 1070, 1165, 1260, 1445,1730, 2860, 2930 and 3200-3600 cm⁻¹ ; ms (70 eV) m/e 406 (p), 388, 357,339, 324, 306, 274, 264, 232.

TR 4807-[α]_(D) +71.1° (c 1.0, CHCl₃); R_(f) (system II) 0.57; nmr(CDCl₃) δ 1.0-2.6 (28H, m), 3.26 (1H, m), 3.64 (3H, s), 5.58 (2H, m),6.11 (1H, m) and 7.47 ppm (1H, m); ir (CHCl₃) 970, 1070, 1220, 1370,1440, 1710, 2860, 2930 and 3200-3600 cm⁻¹ ; ms (70 eV) m/e 388 (p), 356,339, 306, 274, 232, 204.

EXAMPLE 22 Methyl11α,16RS-dihydroxy-16,18-methano-17,20-methano-9-oxoprost-13E-en-1-oateand Methyl16RS-hydroxy-16,18-methano-17,20-methano-9-oxoprosta-10,13E-dien-1-oate(TR 4809 and TR 4801)

The method described in Example 21 was used to preparebicyclo[3.2.0]heptan-6-one by replacing the bicyclo[4.2.0]oct-2-en-7-onewith bicyclo[3.2.0]hept-2-en-6-one. The bicyclo compound was produced asdescribed by E. J. Corey and T. Ravindranathan, Tetrahedron Letters 4753(1971).

The bicyclo[3.2.0]hept-2-en-6-one had the following spectralcharacteristics: nmr (CDCl₃) δ 2.2-4.2 ppm (6H, m) and 5.83 ppm (2H, m);ir (CHCl₃) 1080, 1150, 1345, 1775, 2860 and 2920 cm⁻¹.

The bicyclo[3.2.0]heptan-6-one had the following spectralcharacteristics: nmr (CDCl₃) δ 1.0-3.8 ppm (m); ir (CHCl₃) 905, 1080,1220, 1385, 1450, 1770, 2870 and 2950 cm⁻¹.

The procedure of Example 19 was followed to obtain the correspondingacetylenic alcohol, the corresponding iodovinyl alcohol and thecorresponding protected iodovinyl alcohol by replacing cyclohexanonewith bicyclo[3.2.0]heptan-6-one. The alcohol had the following spectralcharacteristics: nmr (CDCl₃) δ 1.0-2.2 (11H, m), 2.15 (1H, s) and 2.45ppm (2H, d, J=2.5 Hz); ir (CHCl₃) 910, 1775, 1140, 1265, 1460, 2115(weak), 2870, 2930, 3300, 3200 to 3600 (broad) and 3590 cm⁻¹.

The 6-(3-iodoprop-2E-enyl)bicyclo[3.2.0]heptan-6RS-ol had the followingspectral characteristics: nmr (CDCl₃) δ 1.0-2.0 (10H, m), 2.30 (2H, d,J=6.5 Hz), 2.4 (1H, broad s), 6.13 (1H, d, J=14 Hz) and 6.63 ppm (1H, dof t, J=14, 7 Hz); ir (CHCl₃) 950, 1070, 1200, 1260, 1605, 2850, 2940,3200-3600 (broad) and 3600 cm⁻¹.

The iodovinyl alcohol was protected to yield6-(3-iodoprop-2E-enyl)-6RS-(tetrahydropyranyloxy)bicyclo[3.2.0]heptanehaving the following spectral characteristics: nmr (CDCl₃) δ 1.0-2.7(18H, m), 3.2-4.2 (2H, m), 4.58 (1H, broad s), 6.02 (1H, d, J=14 Hz) and6.2-6.9 ppm (1H, m); ir (CHCl₃) 865, 970, 1010, 1070, 1120, 1180, 1270,1430, 1610, 2850 and 2940 cm⁻¹.

The synthesis of the PGE₁ analogue (TR 4809) was carried out asdescribed in Example 19. A small amount of the PGA₁ prostaglandinanalogue (TR 4801) was produced as a side-product. The prostaglandinanalogues had the following spectral characteristics:

TR 4809-[α]_(D) -48.3° (c 1.0, CHCl₃); R_(f) (system II) 0.44; nmr(CDCl₃) δ 1.0-2.8 (30H, m), 3.66 (3H, s), 4.0 (1H, m), and 5.58 ppm (2H,m); ir (CHCl₃) 970, 1075, 1160, 1240, 1440, 1740, 2860, 2930, and3200-3600 cm⁻¹ ; ms (70 eV) m/e 392 (p), 374, 360, 343, 324, 306, 288,274, 264 232.

TR 4801-[α]_(D) +71.1° (c 1.0, CHCl₃); R_(f) (system II) 0.57; nmr(CDCl₃) δ 1.0-2.8 (27H, m), 3.3 (1H, m), 3.67 (3H, s), 5.62 (2H, m),6.15 (1H, m) and 7.50 ppm (1H, m); ir (CHCl₃) 900, 970, 1020, 1070,1120, 1170, 1210, 1360, 1440, 1710, 2860, 2940 and 3200-3600 cm⁻¹ ; ms(70 eV) m/e 374 (p), 342, 325, 306, 274, 264, 246, 232.

EXAMPLE 23 Methyl11α,16RS-dihydroxy-16,20-methano-17,20-methano-9-oxoprost-13E-en-1-oate(TR 4883)

The methods of Example 19 were used to obtain the correspondingacetylenic alcohol, the corresponding iodovinyl alcohol and thecorresponding protected iodovinyl alcohol by replacing cyclohexanonewith commercial bicyclo[2.2.1]heptan-2-one.

The 2-(prop-2-ynyl)bicyclo[2.2.1]heptan-2RS-ol had the followingspectral characteristics: nmr (CDCl₃) δ 1.0-2.8 (10H, m), 2.03 (1H, t,J=2.2 Hz) and 2.42 ppm (2H, d, J=2.2 Hz); ir (CHCl₃) 995, 1035, 1160,1270, 1735, 2950, 3300 and 3200-3600 cm⁻¹ (broad).

The 2-(3-iodoprop-3E-enyl)bicyclo[2.2.1]heptan-2RS-ol had the followingspectral characteristics: nmr (CDCl₃) δ 0.8-2.6 (13H, m), 6.07 (1H, d,J=14.5 Hz) and 6.60 ppm (1H, d of t, J=14.5, 7 Hz); ir (CHCl₃) 950,1030, 1180, 1205, 1305, 2950 and 3300-3700 cm¹ (broad).

The2-(3-iodoprop-3E-enyl)-2RS-(tetrahydropyranyloxy)bicyclo[2.2.1]heptanehad the following spectral characteristics: nmr (CDCl₃) δ 0.8-2.6 (18H,m), 3.2-4.2 (2H, m), 4.65 (1H, broad s), 6.0 (1H, d, J=14.5 Hz) and6.1-6.9 ppm (1H, m); ir (CHCl₃) 860, 970, 1020, 1070, 1120 and 2940cm⁻¹.

The synthesis of the PGE₁ analogue was carried out as described inExample 15 by replacingtrans-2-(2E-iodoethenyl)-1RS-(tetrahydropyran-2-yloxy)cyclopentane with2-(3-iodoprop-2E-enyl)-2RS-(tetraydropyran-2-yloxy)bicyclo[2.2.1]heptane.The prostaglandin analogue TR 4883 had the following spectralcharacteristics: [α]_(D) -53.0° (c 0.94, CHCl₃); R_(f) (system II) 0.38;nmr (CDCl₃) δ 0.8-2.8 (29H, m), 3.63 (3H, s), 4.1 (1H, m) and 3.60 ppm(2H, m); ir (CHCl₃) 970, 1070, 1160, 1210, 1440, 1740, 2940 and3200-3650 cm⁻¹ ; ms (70 eV) m/e 374 (p-H₂ O).

EXAMPLE 24 Methyl 11α,16R andS-dihydroxy-17,17-propano-9-oxoprost-13E-ene-1-oate (TR 4978 and 4979)

The methods of Example 25 were followed to obtain the correspondingalkylated acid, the corresponding substituted methanol and thecorresponding carboxaldehyde by replacing cyclopentanecarboxylic acidwith commercial cyclobutanecarboxylic acid and also replacing methyliodide with commercial propyl iodide.

The 1-propylcyclobutane-1-carboxylic acid had the following spectralcharacteristics: nmr (CDCl₃) δ 0.7-2.8 (13H, complex m) and 11.2 ppm(1H, s); ir (CHCl₃) 930, 1160, 1230, 1255, 1300, 1330, 1410, 1695 and2400-3500 cm⁻¹.

The intermediate 1-propyl-1-cyclobutanemethanol had the followingspectral characteristics: nmr (CDCl₃) δ 0.8-2.2 (14H, m) and 3.52 ppm(2H, s); ir (CHCl₃) 1005, 1230, 1380, 1460, 2930 and 3200-3600 cm⁻¹.

The 1-propyl-1-cyclobutanecarboxaldehyde had the following spectralcharacteristics: nmr (CDCl₃) δ 0.8-2.6 (13H, m) and 9.60 (1H, s); ir(CHCl₃) 1150, 1190, 1460, 1695 and 2970 cm⁻¹.

The methods of Example 17 were then used to obtain the correspondingacetylenic alcohol, the corresponding iodovinyl alcohol and thecorresponding protected iodovinyl alcohol by replacing cyclohexanonewith 1-propylcyclobutane-1-carboxyaldehyde.

The 5,5-propanooct-1-yn-4RS-ol had the following spectral properties:nmr (CDCl₃) δ 0.8-2.7 (16H, m) and 3.77 ppm (1H, m); ir (CHCl₃) 1060,1220, 1460, 2450, 3300 and 3300-3600 cm⁻¹.

The 4-(1-propylcyclobutyl)-1-iodobut-1E-en-4RS-ol had the followingspectral characteristics: nmr (CDCl₃) δ 0.8-2.5 (16H, m), 3.62 (1H, m),6.13 (1H, d, J=14.5 Hz) and 6.67 ppm (1H, d of t, J=14.5, 7.3 Hz); ir(CHCl₃) 940, 1050, 1230, 1270, 1460, 2950 and 3300-3650 cm⁻¹.

The 4-(1-propylcyclobutyl)-1-iodo-4RS-(2-ethoxyethoxy)-but-1E-ene hadthe following spectral characteristics: nmr (CDCl₃) δ 0.8-2.3 (21H, m),3.6 (3H, m), 4.7 (1H, m), 6.05 (1H, d, J=14.5 Hz) and 6.6 ppm (1H, d oft, J=14.5, 7.3 Hz); ir (CHCl₃) 950, 1020, 1050, 1090, 1115, 1380 and2940 cm⁻¹.

The synthesis of the PGE₁ analogue was carried out as described inExample 15. The prostaglandin analogue isomers were separated by columnchromatography and had the following spectral characteristics:

TR 4979-Polar Isomer: [α]_(D) -56.0° (c 1.01, CHCl₃); R_(f) (system II)0.46; nmr (CDCl₃) δ 0.8-2.8 (33H, m), 3.62 (3H, s), 3.3-4.3 (2H, m) and5.01 ppm (2H, m); ir (CHCl₃) 965, 1070, 1160, 1210, 1440, 1740, 2940 and3200-3650 cm⁻¹ ; ms (70 eV) m/e 390 (p-H₂ O).

TR 4978-Less Polar Isomer: [α]_(D) -43.5° (c 1.30, CHCl₃); R_(f) (systemII) 0.47; nmr, ir and ms essentially the same as for the isomer TR 4979above.

EXAMPLE 25 Methyl11α,16R-dihydroxy-17,20-methano-17-methyl-9-oxoprost-13E-en-1-oate andMethyl11α,16S-dihydroxy-17,20-methano-17-methyl-9-oxoprost-13E-en-1-oate (TR4980 and TR 4981)

A solution of 53 g (0.525 mol) of dry diisopropylamine in 417 ml of drytetrahydrofuran was stirred under argon with an external -10° bath as331 ml (0.530 mol) of a solution of n-butyllithium (1.6M) in hexane wasadded fast dropwise. The resultant solution was stirred with cooling for15 minutes. A solution of 28.5 g (0.25 mol) of commercialcyclopentanecarboxylic acid in 42 ml of dry tetrahydrofuran was thenadded dropwise to the stirred, cooled reaction mixture. The resultantsolution was then stirred 15 minutes at 0°. A 53.2 g (0.375 mol) portionof commercial methyliodide was then added slowly dropwise to thestirred, cooled reaction mixture. The ice bath was then removed, and thereaction mixture was stirred at room temperature for 2 hours. Theresultant solution was quenched by the addition of 10% hydrochloricacid, until an acidic aqueous phase was observed. The phases wereseparated after addition of ether, and the aqueous phase was backextracted with ether twice. The combined ether extract was washed withbrine, dried (MgSO₄) and evaporated in vacuo to yield 34.2 g of a redoil. This product was distilled (water pump vacuum) to yield a redpurified product, bp 106°-108°. This red oil was dissolved in ether,washed with saturated aqueous sodium thiosulfate solution, dried (MgSO₄)and then evaporated in vacuo to yield 20 g of a pale yellow oil.Examination of the methyl ester of this product indicated that itcontained considerable starting material, cyclopentanecarboxylic acidalong with the desired product. The above procedure was then repeated onthe recovered sample with the change of proportionately less reagentsfor 20 g vs. 28.5 g of starting material, and also the reaction mixturewas stirred 18 hours rather than 2 hours after addition of methyliodide.The yield of pure 1-methylcyclopentane-1-carboxylic acid was 18.1 g:colorless oil; bp 115°-116° (20 mm); nmr (CDCl₃) δ 1.27 (3H, s), 1.0-2.5(8H, m) and 11.2 ppm (1H, s); ir (CHCl₃) 940, 1200, 1280, 1410, 1455,1700 and 2400-3400 cm⁻¹ (broad).

A slurry of 4.02 g of lithium aluminum hydride in 86 ml of ether wasprepared and stirred under argon with cooling at 0° as a solution of18.1 g of 1-methylcyclopentane-1-carboxylic acid in 46 ml of anhydrousether was added dropwise. The resultant mixture was then refluxed for 45minutes. It was re-cooled and then quenched by the careful dropwiseaddition in sequence of 28 ml ethyl acetate, 5.3 ml water, 5.3 ml of 15%NaOH and then 16.1 ml of water. The resultant mixture was filtered andthen the resultant removed gelatanous material rinsed with ether severaltimes. The remaining gel was stirred with Celite and acetone and thenfiltered. The removed solids were then rinsed thoroughly withether/ethyl acetate (1:1). These second acetone/ether/ethyl acetateextracts were kept separate and evaporated in vacuo. The residue wasmixed with ethyl acetate and washed with brine. The remaining organicextract was dried (MgSO₄) and evaporated in vacuo. The original etherfiltrate was separately evaporated in vacuo. The original ether filtrateyielded 8.74 g of product, 1-methylcyclopentanemethanol, and the acetonetreated extract yielded 7.4 g of recovered starting material,1-methylcyclopentanecarboxylic acid. The product alcohol had thefollowing spectral characteristics: nmr (CDCl₃) δ 1.0 (3H, s), 1.0-2.0(8H, m), 2.42 (1H, broad s) and 3.38 ppm (2H, broad s).

Pyridinium chlorochromate was prepared by following the procedure of E.J. Corey and J. W. Suggs, Tetrahedron Letters, 31, 2647 (1975). Asolution of 11.8 g of 1-methylcyclopentanemethanol in 32 ml of anhydrousmethylene chloride was added to a stirred suspension of 39.2 pyridiniumchlorochromate in 312 ml of methylene chloride under argon. Theresultant dark mixture was stirred for 1.5 hours at ambient temperature.A portion of ether was added to the resultant mixture and then thesupernatant was decanted. The remaining dark residue was rinsed severaltimes with ether. The combined ether solutions were filtered through ashort pad of Florisil. The resultant solution was concentrated bydistillation of ether and then the residue was distilled at 110 mm Hg toyield 6.41 g of 1-methylcyclopentanecarboxaldehyde as a colorless oil:bp 98°-100°; nmr (CDCl₃) δ 1.12 (3H, s), 1.0-2.2 (8H, m) and 9.50 ppm(1H, s).

The methods of Example 17 were used to obtain the correspondingacetylenic alcohol, the corresponding iodovinyl alcohol and thecorresponding protected iodovinyl alcohol by replacing cyclohexanonewith 1-methylcyclopentanecarboxaldehyde.

The 4-(1-methylcyclopentyl)but-1-yn-4RS-ol had the following spectralcharacteristics: nmr (CDCl₃) δ 0.93 (3H, s), 1.0-2.5 (11H, m), 3.0 (1H,broad s) and 3.6 ppm (1H, m); ir (CHCl₃) 840, 1060, 1200, 1380, 1450,1660, 2950, 3300 and 3300-3650 cm⁻¹.

The 4-(1-methylcyclopentyl)-1-iodobut-1E-en-4RS-ol had the followingspectral characteristics: nmr (CDCl₃) δ 0.93 (3H, s), 1.0-2.4 (11H, m),3.43 (1H, m), 6.12 (1H, d, J=14.5 Hz) and 6.70 ppm (1H, d of t, J=14.5,7.2 Hz); ir (CHCl₃) 945, 1060, 1270, 1380, 1450, 2960 and 3300-3600 cm¹.

The 4-(1-methylcyclopentyl)-1-iodo-4RS-(2-ethoxyethoxy)but-1E-ene hadthe following spectral characteristics: nmr (CDCl₃) δ 0.90 (3H, s),1.0-2.0 (14H, m), 2.30 (2H, t, J=6.2 Hz), 3.2-3.9 (3H, m), 4.75 (1H, m),6.10 (1H, d, J=14.5 Hz) and 6.3-7.1 ppm (1H, m); ir (CHCl₃) 950, 1050,1090, 1120, 1380, 1450 and 2950 cm⁻¹.

The synthesis of the PGE₁ analogue was carried out as described inExample 15 by replacingtrans-2-(2E-iodoethanyl)-1RS-(tetrahydropyran-2-yloxy)cyclopentane with4-(1-methylcyclopentyl)-1-iodo-4RS(2-ethoxyethoxy)but-1E-ene. Theprostaglandin analogue isomers TR 4980 and TR 4981 were separated bychromatography and had the following spectral characteristics:

TR4981-Polar Isomer: [α]_(D) -63.6° (c 0.92, CHCl₃); R_(f) (system II)0.47; nmr (CDCl₃) δ 0.97 (3H, s), 1.02-2.8 (28H, m), 3.2-4.3 (2H, m),3.8 (3H, s) and 5.68 ppm (2H, m); ir (CHCl₃) 965, 1070, 1160, 1220,1440, 1740, 2940 and 3200-3650 cm⁻¹ ; ms (70 eV) m/e 376 (p-H₂ O).

TR 4980-Less Polar Isomer: [α]_(D) -47.1° (c 0.98, CHCl₃); R_(f) (systemII) 0.48; nmr, ir and ms much the same as for the isomer TR 4981.

The experimental test data summarized in Table I indicates that theclaimed 16-hydroxy PGE₁ ester analogues all have utility as gastricantisecretory agents or bronchodilators. All of the compounds exhibit adesired separation of biological activity, in particular with regard to0 or low values in the cascade assay tests.

                                      TABLE I                                     __________________________________________________________________________                                  Feline                                                                        Blood     Blood              Plate-             Exam-                                                                             TR  Cascade      Rat Guinea                                                                             Pressure,                                                                          Femoral                                                                            Pressure                                                                            Gastric      let                ple Num-                                                                              Stom-                                                                             Co-                                                                              Rec-                                                                             Aor-                                                                             Uter-                                                                             Pig  Heart                                                                              Blood                                                                              Hyperten-                                                                           Secre-                                                                            Antagonism                                                                             Aggre-             No. ber ach lon                                                                              tum                                                                              ta us  Trachea                                                                            Rate Flow sive Rat                                                                            tion                                                                              PGE1                                                                              PGF2A                                                                              gation             __________________________________________________________________________    17  4839                                                                              0   0  0  0  0   R1   --   --   --    1   --  0    +1                 18  4767                                                                              2   0  1  0  0   R0   0    0    0     0   0   0    +2                     4768                                                                              1   0  1  0  0   R2   --   --   --    0   0   0    +2                 19  4717                                                                              1   0  0  0  0   R3   1    2    0     3   1   0    +1                 20  4800                                                                              0   0  0  0  0   R4   0    1    0     3   0   0    +1                     4802                                                                              0   0  0  0  0   R0   --   --   --    0   0   0    +1                 21  4808                                                                              0   0  0  0  0   R0   0    0    0     1   0   0    +1                     4807                                                                              0   0  0  0  0   R0   --   --   --    0   0   0    +1                 22  4809                                                                              0   0  0  0  0   R4   --   --   --    3   1   0    +1                     4801                                                                              0   0  0  0  0   R0   --   --   --    0   0   0    +1                 23  4883                                                                              0   0  0  0  0   R4   1    --   1     3   0   0    +2                 24  4978                                                                              --  -- -- -- --  R4   --   --   --    0   --  --   +1                     4979                                                                              --  -- -- -- --  R3   --   --   --    0   --  --   +1                 25  4980                                                                              0   0  0  -- --  R2   --   --   --    0   --  --   +1                     4981                                                                      __________________________________________________________________________

What is claimed is:
 1. A therapeutic method for inhibiting gastricsecretion in an individual to whom such therapy is indicated,comprising: administering to the individual an effective gastricinhibiting amount of methyl11α,16RS-dihydroxy-16,20-methano-9-oxoprost-13E-en-1-oate.
 2. Atherapeutic method for inhibiting gastric secretion in an individual towhom such therapy is indicated, comprising: administering to theindividual an effective gastric inhibiting amount of methyl11α,16RS-dihydroxy-16,18-methano-17,20-methano-9-oxoprosta-13E,19-dien-1-oate.3. A therapeutic method for inhibiting gastric secretion in anindividual to whom such therapy is indicated, comprising: administeringto the individual an effective gastric inhibiting amount of methyl11α,16RS-dihydroxy-16,18-methano-17,20-methano-9-oxoprost-13E-en-1-oate.4. A therapeutic method for inhibiting gastric secretion in anindividual to whom such therapy is indicated, comprising: administeringto the individual an effective gastric inhibiting amount of methyl11α,16RS-dihydroxy-16,20-methano-17,20-methano-9-oxoprost-13E-en-1-oate.